Article

Long term effect and safety of Wharton's jelly-derived mesenchymal stem cells on type 2 diabetes

July 2016
Experimental and Therapeutic Medicine 12(3)

DOI:10.3892/etm.2016.3544

Authors:

Cellular therapies offer novel opportunities for the treatment of type 2 diabetes mellitus (T2DM). The present study evaluated the long-term efficacy and safety of infusion of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) on T2DM. A total of 61 patients with T2DM were randomly divided into two groups on the basis of basal therapy; patients in group I were administered WJ-MSC intravenous infusion twice, with a four-week interval, and patients in group II were treated with normal saline as control. During the 36-month follow-up period, the occurrence of any adverse effects and the results of clinical and laboratory examinations were recorded and evaluated. The lack of acute or chronic adverse effects in group I was consistent with group II.. Blood glucose, glycosylated hemoglobin, C-peptide, homeostasis model assessment of pancreatic islet β-cell function and incidence of diabetic complications in group I were significantly improved, as compared with group II during the 36-month follow-up. The results of the present study demonstrated that infusion of WJ-MSC improved the function of islet β-cells and reduced the incidence of diabetic complications, although the precise mechanisms are yet to be elucidated. The infusion of WJ-MSC may be an effective option for the treatment of patients with type 2 diabetes.

Effectiveness and safety of stem cells in the treatment of diabetes

Article

Full-text available

Jan 2023

Diabetes mellitus type 1 (DM1) and type 2 (DM2) is one of the most common chronic diseases with high rates of morbidity and mortality. Insulin replacement therapy and other various hypoglycemic means have been used for more than 90 years to control high blood glucose levels, but they cannot accurately mimic the secretion of endogenous insulin, can cause reactive hypoglycemia, and do not exclude the risk of secondary complications of diabetes (nephropathy, neuropathy, retinopathy, vascular pathology). The introduction of new scientific achievements into clinical practice in the future allows optimizing the treatment for diabetes and its complications, which can significantly improve the quality of life of many patients. A very promising method of DM therapy is the use of stem cells (SC) as an almost unlimited source of physiologically competent substitute for primary islets of Langerhans. SC can transform (specialize) into any cell of the body and, unlike others, can divide an indefinite number of times. This allows SC to maintain a certain number of their population and allows for the formation of a whole hierarchy of SC in the body, which are stored in certain depots. And, finally, SC are characterized by the Homing effect — the ability to find the damaged zone and fix itself in it, filling the lost function when introduced into the body. A number of studies and recent meta-analyses suggest that C-peptide, HbA1c levels, and daily insulin requirements improve after treatment of DM with stem cells, meaning that SC therapy may be a safe and effective intervention for some individuals with DM. In DM1, bone marrow hematopoietic SC are a good source of SC transplantation. In DM2, HbA1c and daily insulin requirements were significantly improved after mesenchymal SC therapy, and bone marrow mononuclear cell therapy significantly reduced insulin requirements and improved C-peptide levels. These encouraging results require confirmation in large, randomized, double-blind studies, as well as with longer follow-up periods to clearly recommend stem cell-based therapy as the standard of DM management.

Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up

Article

Full-text available

Sep 2022

Background Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization. Methods In this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 10 ⁵ cells/kg with an upper limit of 1 × 10 ⁷ cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase. Results The safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments. Conclusions Based on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing. Trial registration : The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888 Graphical Abstract

Efficacy of mesenchymal stem cell transplantation therapy for type 1 and type 2 diabetes mellitus: a meta-analysis

Article

Full-text available

May 2021

Background This meta-analysis was first conducted to evaluate the efficacy and safety of transplantation of mesenchymal stem cells in the treatment of type 1 and type 2 diabetes mellitus (T1DM and T2DM). Methods We systematically searched PubMed, ScienceDirect, Google Scholar, CNKI, EMBASE, Web of Science, MEDLINE, and the Cochrane Library for studies published from the establishment of the databases to November 2020. Two researchers independently screened the identified studies, based on inclusion and exclusion criteria. The combined standard mean difference (SMD) and 95% confidence interval (CI) of data from the included studies were calculated using fixed- or random-effects models. Results We included 10 studies in our meta-analysis (4 studies on T1DM and 6 on T2DM, with 239 participants) to examine the efficacy of mesenchymal stem cells (MSCs) therapy in the treatment of diabetes mellitus. According to the pooled estimates, the glycated hemoglobin (HbA1c) level of the MSC-treated group was significantly lower than it was at baseline (mean difference (MD) = −1.51, 95% CI −2.42 to −0.60, P = 0.001). The fasting C-peptide level of the MSC-treated group with T1DM was higher than that of the control group (SMD = 0.89, 95% CI 0.36 to 1.42, P = 0.001), and their insulin requirement was significantly lower than it was at baseline (SMD = −1.14, 95% CI −1.52 to −0.77, P < 0.00001). Conclusion Transplantation of mesenchymal stem cells has beneficial effects on diabetes mellitus, especially T1DM, and no obvious adverse reactions.

Clinical efficacy on glycemic control and safety of mesenchymal stem cells in patients with diabetes mellitus: Systematic review and meta-analysis of RCT data

Article

Full-text available

Mar 2021
PLOS ONE

Background Diabetes mellitus as a chronic metabolic disease is threatening human health seriously. Although numerous clinical trials have been registered for the treatment of diabetes with stem cells, no articles have been published to summarize the efficacy and safety of mesenchymal stem cells (MSCs) in randomized controlled trials (RCTs).Methods and findingsThe aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to provide a reliable numerical summary and the most comprehensive assessment of therapeutic efficacy and safety with MSCs in diabetes. PubMed, Web of Science, Ovid, the Cochrane Library and CNKI were searched. The retrieval time was from establishment of these databases to January 4, 2020. Seven RCTs were eligible for analysis, including 413 participants. Meta-analysis results showed that there were no significant differences in the reduction of fasting plasma glucose (FPG) compared to the baseline [mean difference (MD) = -1.05, 95% confidence interval (CI) (-2.26,0.16), P

Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth Infusion into Patients with Type 2 Diabetes Depends on Basal Lipid Levels and Islet Function

Article

Full-text available

Mar 2021

Mesenchymal stem cells (MSCs) hold great potential in treating patients with diabetes, but the therapeutic effects are not always achieved. Particularly, the clinical factors regulating MSC therapy in this setting are largely unknown. In this study, 24 patients with type 2 diabetes mellitus (T2DM) treated with insulin were selected to receive three intravenous infusions of stem cells from human exfoliated deciduous teeth (SHED) over the course of 6 weeks and were followed up for 12 months. We observed a significant reduction of glycosylated serum albumin level (P < .05) and glycosylated hemoglobin level (P < .05) after SHED transplantation. The total effective rate was 86.36% and 68.18%, respectively, at the end of treatment and follow‐up periods. Three patients ceased insulin injections after SHED transplantation. A steamed bread meal test showed that the serum levels of postprandial C‐peptide at 2 hours were significantly higher than those at the baseline (P < .05). Further analysis showed that patients with a high level of blood cholesterol and a low baseline level of C‐peptide had poor response to SHED transplantation. Some patients experienced a transient fever (11.11%), fatigue (4.17%), or rash (1.39%) after SHED transplantation, which were easily resolved. In summary, SHED infusion is a safe and effective therapy to improve glucose metabolism and islet function in patients with T2DM. Blood lipid levels and baseline islet function may serve as key factors contributing to the therapeutic outcome of MSC transplantation in patients with T2DM. Stem cells from human exfoliated deciduous teeth (SHED) infusion is a safe and effective therapy to improve glucose metabolism and islet function in type 2 diabetes mellitus (T2DM) patients. Blood lipid levels and baseline islet function may serve as a key factors contributing to the therapeutic outcome of mesenchymal stem cells transplantation in T2DM patients.

Therapeutic efficacy of umbilical cord- derived stem cells for diabetes mellitus: a meta-analysis study

Article

Full-text available

Nov 2020

Background Stem cell therapy provides great hope for patients with diabetes mellitus (DM). DM is a seriously alarming metabolic disease characterized by hyperglycemia and β cell dysfunction. Efficient novel therapeutic modalities to treat DM are indeed warranted. Stem cells (SC) derived from the umbilical cord specifically provide several advantages and unique characteristics being a readily available non-invasive source, with an additional credit for their banking potential. This meta-analysis study aims to provide a focused assessment for therapeutic efficacy of umbilical cord (UC)-derived SC-transplantation, namely Wharton’s jelly mesenchymal stem cells (WJ-MSCs) and umbilical cord blood (UCB) for DM. Methods The clinical efficacy was evaluated based on glycemic control status (reflected on HbA1c%) and β cell function (reflected on C-peptide levels), as well as the daily insulin requirement in diabetic patients after receiving UC-derived SC-transplantation compared to baseline values. Moreover, we assessed these outcome measures in patients who received such intervention compared to those who did not receive it in randomized/non-randomized controlled clinical trials. We employed a random-effects model and standardized mean difference for this meta-analysis. Results Eleven eligible clinical studies were included; WJ-MSCs (6 studies; 172 patients including 71 controls) and UCB (5 studies; 74 patients including 15 controls). WJ-MSCs significantly improved HbA1c% (pooled-estimate − 1.085; 95%CI (− 1.513, − 0.657); p < 0.001) and C-peptide levels (pooled-estimate 1.008; 95%CI (0.475, 1.541); p < 0.001), as well as the daily insulin-requirement (pooled-estimate − 2.027; 95%CI (− 3.32, − 0.733); p = 0.002). On the contrary, UCB was found to be uniformly ineffective; HbA1c% (pooled-estimate − 0.091, 95%CI (− 0.454, 0.271); p = 0.622), significantly deteriorated C-peptide levels (pooled-estimate − 0.789; 95%CI (− 1.252, − 0.325); p < 0.001) and daily insulin-requirement (pooled-estimate 0.916; 95%CI (0.247, 1.585); p = 0.007). All these observations remained consistent when we carried out sub-group meta-analysis for T1DM and T2DM and also when we compared patients who received WJ-MSCs or UCB to controls. Conclusions The results of our meta-analysis provide a clear evidence for the superior efficacy of WJ-MSCs over UCB in DM. This sheds lights on the importance to consider banking of WJ-MSCs together with the well-established routine UCB-banking, especially for those with family history of DM. Additionally, further clinical studies are required to investigate therapeutic efficacy of selected/enriched UCB-derived cell populations with immunomodulatory/regenerative potential in DM.

Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis

Article

Full-text available

Jan 2020

Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012-2019, we performed an updated systematic review to further characterize the MSC safety profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. Findings: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2·48, 95% Confidence Interval (CI) = 1·27-4·86; I2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/embolic events, death, or malignancy (RR = 1·16, 0·99, 1·14, 0·78, 0·93; 95% CI = 0·70-1·91, 0·81-1·21, 0·67-1·95, 0·65-0·94, 0·60-1·45; I2 = 0%, 0%, 0%, 0%, 0%). No included trials were ended prematurely due to safety concerns. Interpretations: MSC therapy continues to exhibit a favourable safety profile. Future trials should continue to strengthen study rigor, reporting of MSC characterization, and adverse events. Funding: Stem Cell Network, Ontario Institute for Regenerative Medicine and Ontario Research Fund.

Glycemic Control by Umbilical Cord-Derived Mesenchymal Stem Cells Promotes Effects of Fasting-Mimicking Diet on Type 2 Diabetes

Preprint

Full-text available

Feb 2021

Background Hepatic steatosis is a big hurdle to treat type 2 diabetes (T2D). Fasting-mimicking diet (FMD) has been shown to be an effective intervention in dyslipidemia of T2D. However, fasting might impair the normal glucose metabolism. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation has been discovered to regulate immune reactions and reduce hyperglycemia in diabetes. However, the effects of UC-MSCs on improving the lipid metabolism disorder are not quite satisfactory. We have investigated the efficacy comparison and interaction between two typical therapies of FMD and UC-MSC infusion, aiming to pave an avenue for their synergistic use, establish effective T2D therapies and explore its mechanism. Methods C57/BL6 mice were fed with high-fat diet (HFD) for 16 weeks to induce a diet-induced obese (DIO) mouse model. Six-week-old leptin-receptor-deficient (db/db) mice were used for follow-up experiments. DIO or db/db mice were divided into 4 groups: PBS, UC-MSCs (1*10⁶), FMD (entails 4-day FMD and 7-day of refeeding (RF)) and UC-MSCs + FMD. At the end of the study period, mice were fasted for 6 h with the measurement of blood glucose and body weight, and then sacrificed. Blood was collected to determine levels of HbA1c, serum insulin, and cytokines. In addition, the fresh liver, skin and white adipose tissue were analyzed by histology. Results FMD restored the lipid metabolism in DIO mice, whereas its capacity to rescue hyperglycemia was uncertain. Infusion of UC-MSCs was effective in T2D glycemic control but the impact on dyslipidemia was insufficient. Furthermore, both the glucose and the lipid alterations of DIO and db/db mice recovered after UC-MSCs combined with FMD. It was proved that UC-MSCs promoted FMD effects on ameliorating hyperglycemia and restoring the lipid metabolism in T2D mice, while FMD had little promotion effect on UC-MSCs. Mechanistically, we discovered that UC-MSC infusion significantly modulated systematic inflammatory microenvironment, which contributed to concerted actions with FMD. Conclusions We established a strategy that combined UC-MSC infusion and FMD were effective in treating T2D, which synergistically attenuated hyperglycemia and improved the lipid metabolism through immunoregulation. The significance of the work is to provide potential approaches for developing novel clinical T2D therapies.

Prospective Utilization of Wharton’s Jelly-Derived Mesenchymal Stem Cells and Their Conditioned Medium in the Regeneration of Diabetic Corneal Neuropathy

Article

Full-text available

Jan 2022

Pitra Ariesta Shinta Dewi

Regulación de la función inmunitaria por células mesenquimales

Article

May 2022

Safety study of allogeneic mesenchymal stem cell therapy in animal model

Article

Full-text available

Mar 2022

Intravenous (IV) infusion of mesenchymal stem cells (MSCs) from nascent tissues like Wharton's Jelly of the umbilical cord is reported to offer therapeutic effects against chronic diseases. However, toxicological data essential for the clinical application of these cells are limited. Thus, this study aimed to determine the safety of IV infusion of Wharton's Jelly derived MSCs (WJ-MSCs) in rats. Fifteen male Sprague–Dawley rats were randomised into the control or treatment group. Each group received an equal volume of saline or WJ-MSC (10 × 10⁶ cell/kg) respectively. The animals were evaluated for physical, biochemical and haematological changes at Week 0, 2, 4, 8 and 12 during the 12-week study. Acute toxicity was performed during Week 2 and sub-chronic toxicity during Week 12. At the end of the study, the relative weight of organs was calculated and histology was performed for lung, liver, spleen and kidney. The findings from physical, serum biochemistry and complete blood count demonstrated no statistically significant differences between groups. However, pathological evaluation reported minor inflammation in the lungs for all groups, but visible healing and resolution of inflammation were observed in the treatment group only. Additionally, the histological images of the treatment group had significantly improved pulmonary structures compared to the control group. In summary, the IV administration of WJ-MSC was safe in the rats. Further studies are needed to determine the long-term safety of the WJ-MSC in both healthy and diseased animal models.

Diabetes duration and obesity matter in autologous mesenchymal stem/stromal cell transplantation in type 2 diabetes patients

Article

Full-text available

Dec 2021

Type 2 diabetes develops due to functional β cell loss after insulin resistance. Sustained increased insulin demand compels β cells into apoptosis and dedifferentiation resulting in decreased β cell mass. In adult humans, β cell regeneration (proliferation, neogenesis or transdifferentiation) rarely occurs in a physiologic condition. Because of this stagnant nature of β cells, β cell mass are not sufficiently recovered once their numbers are severely decreased. Constant efforts have been made to replenish the decreased β cell mass in diabetic patients by islet or pancreas transplantation1,2.

Impact of Type 2 Diabetes Mellitus on the Immunoregulatory Characteristics of Adipose Tissue-Derived Mesenchymal Stem Cells

Article

Aug 2021
INT J BIOCHEM CELL B

Background Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with several complications. Adipose-tissue–derived mesenchymal stem cells (AT-MSCs) possess high plasticity and differentiation capabilities and are useful for treating inflammation-related disorders such as T2DM. However, the pathogenic microenvironment of T2DM may affect their therapeutic potential. We aimed to examine the impact of the diabetic milieu on the immunomodulatory/anti-inflammatory potential of AT-MSCs. Methods We assessed the proliferation potential, cell surface expression of MSC-characteristic markers and immunomodulatory markers, along with the gene expression and secretion of pro-inflammatory and anti-inflammatory cytokines and adipokines in AT-MSCs derived from T2DM patients (dAT-MSCs) vs. non-diabetic volunteers (ndAT-MSCs). Furthermore, we evaluated the IFN-γ priming effect on both groups. Results Our data revealed comparable proliferative activities in both groups. Elevated IL-1β mRNA expression associated with a downregulation of IL-1RN was observed in dAT-MSCs vs. ndAT-MSCs. Flow cytometric analysis results showed a lower expression of CD200 and CD276 on dAT-MSCs relative to ndAT-MSCs. IFN-γ priming induced an elevation in CD274 expression associated with IDO1 and ILRN overexpression and IL-1β downregulation in both groups. Enzyme-linked immunosorbent assay (ELISA) uncovered elevated levels of secreted IL-1β, TNF, and visfatin/NAMPT in dAT-MSCs, whereas IL-1RA and IDO levels were reduced. ELISA results were also evident in the secretome of dAT-MSCs upon IFN-γ priming. Conclusions This study suggests that the T2DM milieu alters the immunomodulatory characteristics of AT-MSCs with a shift towards a proinflammatory phenotype which may restrain their autologous therapeutic use. Furthermore, IFN-γ priming could be a useful strategy for enhancing their anti-inflammatory potential.

The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice

Article

Full-text available

Jul 2021

Background The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton’s jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice. Methods Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations. Results UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively. Conclusions Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.

Type 2 Diabetes Mellitus Duration and Obesity alter the Efficacy of Autologously Transplanted Bone Marrow-derived Mesenchymal Stem/Stromal Cells

Article

Full-text available

Jun 2021

Human bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) represent promising stem cell therapy for the treatment of type 2 diabetes mellitus (T2DM), but the results of autologous BM-MSC administration in T2DM patients are contradictory. The purpose of this study was to test the hypothesis that autologous BM-MSC administration in T2DM patient is safe and that the efficacy of the treatment is dependant on the quality of the autologous BM-MSC population and administration routes. T2DM patients were enrolled, randomly assigned (1:1) by a computer-based system into the intravenous and dorsal pancreatic arterial groups. The safety was assessed in all the treated patients, and the efficacy was evaluated based on the absolute changes in the hemoglobin A1c, fasting blood glucose, and C-peptide levels throughout the 12-month follow-up. Our data indicated that autologous BM-MSC administration was well tolerated in 30 T2DM patients. Short-term therapeutic effects were observed in patients with T2DM duration of <10 years and a body mass index <23, which is in line with the phenotypic analysis of the autologous BM-MSC population. T2DM duration directly altered the proliferation rate of BM-MSCs, abrogated the glycolysis and mitochondria respiration of BM-MSCs, and induced the accumulation of mitochondria DNA mutation. Our data suggest that autologous administration of BM-MSCs in the treatment of T2DM should be performed in patients with T2DM duration <10 years and no obesity. Prior to further confirming the effects of T2DM on BM-MSC biology, future work with a larger cohort focusing on patients with different T2DM history is needed to understand the mechanism underlying our observation. Liem Thanh Nguyen and Duc M. Hoang contributed equally to this study.

Stem Cells: Novel Technologies, Therapies and Industrial Models

Chapter

May 2021

Stem cells are a kind of cells with the ability of self-renewal and multi-directional differentiation potential. A variety of stem cells or progenitor cells have been shown to be efficacy in the treatment of some refractory diseases. The mesenchymal stem cells (MSCs) are derived from mesoderm and have the characteristics of differentiation into three germ layers and immune regulation, which means that these cells are suitable for either autologous or allogeneic treatment and are ideal cells for regenerative medicine. MSCs can be isolated from various tissue types, including the bone marrow, fat, and perinatal tissues. From the perspective of ethics, medicine and cell engineering, adult bone marrow and adipose MSCs cannot be used as a mass production source of conventional treatment. Perinatal tissue, including umbilical cord, amniotic fluid and placenta, is a rich source of MSCs with strong immunosuppressive and proangiogeneic activities. These stem cells bring new hope for disease treatment. This paper reviews the research progress of stem cells as novel technology, novel therapies and industrial model in the field of regenerative medicine.

Allogenic Use of Human Placenta-Derived Stromal Cells as a Highly Active Subtype of Mesenchymal Stromal Cells for Cell-Based Therapies

Article

Full-text available

May 2021
INT J MOL SCI

The application of mesenchymal stromal cells (MSCs) from different sources, including bone marrow (BM, bmMSCs), adipose tissue (atMSCs), and human term placenta (hPSCs) has been proposed for various clinical purposes. Accumulated evidence suggests that the activity of the different MSCs is indirect and associated with paracrine release of pro-regenerative and anti-inflammatory factors. A major limitation of bmMSCs-based treatment for autologous application is the limited yield of cells harvested from BM and the invasiveness of the procedure. Similar effects of autologous and allogeneic MSCs isolated from various other tissues were reported. The easily available fresh human placenta seems to represent a preferred source for harvesting abundant numbers of human hPSCs for allogenic use. Cells derived from the neonate tissues of the placenta (f-hPSC) can undergo extended expansion with a low risk of senescence. The low expression of HLA class I and II on f-hPSCs reduces the risk of rejection in allogeneic or xenogeneic applications in normal immunocompetent hosts. The main advantage of hPSCs-based therapies seems to lie in the secretion of a wide range of pro-regenerative and anti-inflammatory factors. This renders hPSCs as a very competent cell for therapy in humans or animal models. This review summarizes the therapeutic potential of allogeneic applications of f-hPSCs, with reference to their indirect pro-regenerative and anti-inflammatory effects and discusses clinical feasibility studies.

Cytohistologic analyses of β cell dedifferentiation induced by inflammation in human islets

Article

Full-text available

May 2021
EUR J INFLAMM

β cell dedifferentiation is a key mechanism for β cell dysfunction in type 2 diabetes mellitus (T2DM). Although it has been indicated in previous studies that β cell dedifferentiation could be induced by inflammation, the cytohistologic analyses of inflammation-induced β cell dedifferentiation in human islets is lacking. The present study aims to cytohistologically characterize the β cell dedifferentiation of human islets treated by proinflammatory cytokines Interleukin-1β/Tuman necrosis factor-α/Interferon-γ (IL-1β/TNF-α/IFN-γ), which is a frequently-used method to mimic the islet inflammation in previous studies. The loss of cytosolic FOXO1 expression, the loss of nucleic NKX6.1 expression, and the gain of ALDH1A3 expression in β cells are proclaimed as marking events for β cell dedifferentiation. Taking advantages of islets from organ donors and the immunofluorescence staining methods, the present study visualized the β cell dedifferentiation events marked by different markers, and quantified the frequency of each event as well. We successfully captured and described the characteristics of the differentiating/differentiated β cells. We found that dedifferentiated β cells were increased in the cytokines treated islets, evidenced by the increase of β cells with FOXO1 translocated to the nucleus (INS ⁺ FOXO nuc ), β cells with NKX6.1 exported from the nucleus (INS ⁺ NKX6.1 cyt ), and β cells loss of NKX6.1 expression (INS ⁺ NKX6.1 ⁻ ), and β cells with dual expression of insulin and progenitor marker ALDH1A3. Consistently, we found that proinflammatory cytokines IL-1β/TNF-α/IFN-γ treatment reduced the mRNA expression of key β cell markers, but elevated the expression of progenitor marker genes. This study gives the most direct evidence for inflammation-induced β cell dedifferentiation in human islets, and supports the concept that anti-inflammation treatments may facilitate alleviating the β cell dedifferentiation in human T2DM islets.

Quercetin/Zinc complex and stem cells: A new drug therapy to ameliorate glycometabolic control and pulmonary dysfunction in diabetes mellitus: Structural characterization and genetic studies

Article

Full-text available

Mar 2021
PLOS ONE

Medicinal uses and applications of metals and their complexes are of increasing clinical and commercial importance. The ligation behavior of quercetin (Q), which is a flavonoid, and its Zn (II) (Q/Zn) complex were studied and characterized based on elemental analysis, molar conductance, Fourier-transform infrared (FTIR) spectra, electronic spectra, proton nuclear magnetic resonance ( ¹ H-NMR), thermogravimetric analysis, and transmission electron microscopy (TEM). FTIR spectral data revealed that Q acts as a bidentate ligand (chelating ligand) through carbonyl C(4) = O oxygen and phenolic C(3)–OH oxygen in conjugation with Zn. Electronic, FTIR, and ¹ H-NMR spectral data revealed that the Q/Zn complex has a distorted octahedral geometry, with the following chemical formula: [Zn(Q)(NO 3 )(H 2 O) 2 ].5H 2 O. Diabetes was induced by streptozotocin (STZ) injection. A total of 70 male albino rats were divided into seven groups: control, diabetic untreated group and diabetic groups treated with either MSCs and/or Q and/or Q/Zn or their combination. Serum insulin, glucose, C-peptide, glycosylated hemoglobin, lipid profile, and enzymatic and non-enzymatic antioxidant levels were determined. Pancreatic and lung histology and TEM for pancreatic tissues in addition to gene expression of both SOD and CAT in pulmonary tissues were evaluated. MSCs in combination with Q/Zn therapy exhibited potent protective effects against STZ induced hyperglycemia and suppressed oxidative stress, genotoxicity, glycometabolic disturbances, and structural alterations. Engrafted MSCs were found inside pancreatic tissue at the end of the experiment. In conclusion, Q/Zn with MSC therapy produced a synergistic effect against oxidative stress and genotoxicity and can be considered potential ameliorative therapy against diabetes with pulmonary dysfunction, which may benefit against COVID-19.

Mesenchymal Stromal Cell-Mediated Immune Regulation: A Promising Remedy in the Therapy of Type 2 Diabetes Mellitus

Article

Feb 2021
STEM CELLS

Type 2 diabetes mellitus (T2DM) is a major threat to global public health, with increasing prevalence as well as high morbidity and mortality, to which immune dysfunction has been recognized as a crucial contributor. Mesenchymal stromal cells (MSCs), obtained from various sources and possessing potent immunomodulatory abilities, have displayed great therapeutic potential for T2DM. Interestingly, the immunomodulatory capabilities of MSCs are endowed and plastic. Among the multiple mechanisms involved in MSC-mediated immune regulation, the paracrine effects of MSCs have attracted much attention. Of note, extracellular vesicles (EVs), an important component of MSC secretome, have emerged as pivotal mediators of their immunoregulatory effects. Particularly, the necrobiology of MSCs, especially apoptosis, has recently been revealed to affect their immunomodulatory functions in vivo. In specific, a variety of preclinical studies have demonstrated the beneficial effects of MSCs on improving islet function and ameliorating insulin resistance. More importantly, clinical trials have further uncovered the therapeutic potential of MSCs for T2DM. In this review, we outline current knowledge regarding the plasticity and underlying mechanisms of MSC-mediated immune modulation, focusing on the paracrine effects. We also summarize the applications of MSC-based therapies for T2DM in both preclinical studies and clinical trials, with particular emphasis on the modulation of immune system.

Comparison of similar cells: Mesenchymal stromal cells and fibroblasts

Article

Dec 2020
ACTA HISTOCHEM

Almost from all organs, both mesenchymal stromal cells and fibroblasts can be isolated. Mesenchymal stromal cells (MSCs) are the most preferred cellular therapeutic agents with the regenerative potential, and fibroblasts are one of the most abundant cell types with the ability to maintain homeostasis. Because of the promising properties of MSCs, they have been well studied and their differentiation potentials, immunomodulatory potentials, gene expression profiles are identified. It has been observed that fibroblasts and mesenchymal stromal cells have similar morphology, gene expression patterns, surface markers, proliferation, differentiation, and immunomodulatory capacities. Thus, it is hard to distinguish these two cell types. Epigenetic signatures, i.e., methylation patterns of cells, are the only usable promising difference between them. Such significant similarities show that these two cells may be related to each other.

Diabetes Mellitus Is a Chronic Disease that Can Benefit from Therapy with Induced Pluripotent Stem Cells

Article

Full-text available

Nov 2020

Diabetes mellitus (DM) is one of the main causes of morbidity and mortality, with an increasing incidence worldwide. The impact of DM on public health in developing countries has triggered alarm due to the exaggerated costs of the treatment and monitoring of patients with this disease. Considerable efforts have been made to try to prevent the onset and reduce the complications of DM. However, because insulin-producing pancreatic β-cells progressively deteriorate, many people must receive insulin through subcutaneous injection. Additionally, current therapies do not have consistent results regarding the prevention of chronic complications. Leveraging the approval of real-time continuous glucose monitors and sophisticated algorithms that partially automate insulin infusion pumps has improved glycemic control, decreasing the burden of diabetes management. However, these advances are facing physiologic barriers. New findings in molecular and cellular biology have produced an extraordinary advancement in tissue development for the treatment of DM. Obtaining pancreatic β-cells from somatic cells is a great resource that currently exists for patients with DM. Although this therapeutic option has great prospects for patients, some challenges remain for this therapeutic plan to be used clinically. The purpose of this review is to describe the new techniques in cell biology and regenerative medicine as possible treatments for DM. In particular, this review highlights the origin of induced pluripotent cells (iPSCs) and how they have begun to emerge as a regenerative treatment that may mitigate the pathology of this disease.

High Dose of Intravenous Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells (CLV-100) Infusion Displays Better Immunomodulatory Effect among Healthy Volunteers: A Phase 1 Clinical Study

Article

Full-text available

Sep 2020

Background. Mesenchymal stem cells (MSCs) express growth factors and other cytokines that stimulate repair and control the immune response. MSCs are also immunoprivileged with low risk of rejection. Umbilical cord-derived MSCs (UCMSCs) are particularly attractive as an off-the-shelf allogeneic treatment in emergency medical conditions. We aim to determine the safety and efficacy of intravenous allogeneic infusion of UCMSCs (CLV-100) by Cytopeutics® (Selangor, Malaysia) in healthy volunteers, and to determine the effective dose at which an immunomodulatory effect is observed. Methodology. Umbilical cord samples were collected after delivery of full-term, healthy babies with written consent from both parents. All 3 generations (newborn, parents, and grandparents) were screened for genetic mutations, infections, cancers, and other inherited diseases. Samples were transferred to a certified Good Manufacturing Practice laboratory for processing. Subjects were infused with either low dose (LD, 65 million cells) or high dose (HD, 130 million cells) of CLV-100 and followed up for 6 months. We measured cytokines using ELISA including anti-inflammatory cytokines interleukin 1 receptor antagonist (IL-1RA), interleukin 10 (IL-10), pro-/anti-inflammatory cytokine interleukin 6 (IL-6), and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Results. 11 healthy subjects (LD, ; HD, ; mean age of years) were recruited. All subjects tolerated the CLV-100 infusion well with no adverse reaction throughout the study especially in vital parameters and routine blood tests. At 6 months, the HD group had significantly higher levels of anti-inflammatory markers IL1-RA ( vs. ; ) and IL-10 ( vs. L; ); and lower levels of proinflammatory marker TNF-α ( vs. ; ) compared to LD group. Conclusion. Allogeneic UCMSCs CLV-100 infusion is safe and well-tolerated in low and high doses. Anti-inflammatory effect is observed with a high-dose infusion. 1. Introduction Mesenchymal stem cells (MSCs) are multipotent fibroblast-like cells that reside in various tissues of the human body. MSCs have the capacity to regenerate and replicate as well as to differentiate into various specialized cells and tissues in the body, including chondrocytes, adipocytes, osteocytes, and neuron-like cells [1–3]. The self-renewal and multilineage potentials of MSCs in providing new cells for tissue repair by replacing the damaged cells suggest its therapeutic potentials in tissue regeneration [2, 4–8]. Several studies have reported that the mechanism of MSCs in repairing tissue damage is associated to their immunomodulatory properties rather than its capacity for differentiation [9, 10]. One of MSCs’ vital biological function, the immunomodulation, provides MSCs with the ability to migrate and adhere to any injury or inflammation sites found in the body and thereby interact with various immune cells such as T cells, B cells, natural killer cells, dendritic cells, neutrophils, and macrophages before evoking effective immune responses to ameliorate the intense inflammatory reaction of the injured site via direct cell-cell contact mechanism and/or the release of soluble inducible factors [11–13]. MSCs can be isolated from various tissues including bone marrow, peripheral blood, adipose tissue, cord blood, and umbilical cord. Recent studies have shown that MSCs derived from human umbilical cord (UCMSCs) possess several advantages compared to MSCs isolated from other tissues, including high-proliferation and self-renewal capacity and multilineage differentiation capability. Umbilical cord is considered as a medical waste, and the collection of UC-MSCs is noninvasive which eliminates any ethical concern from its collection. [14, 15]. In addition, UCMSCs possess low immunogenicity allowing them to be utilized in allogeneic transplantation without any rejection and thereby providing a new approach for the treatment of autoimmune diseases [16]. Consequently, UCMSCs have been developed as an “off-the-shelf” cell therapy for a variety of diseases especially in autoimmune diseases. Clinical studies in graft-versus-host disease (aGVHD) have demonstrated that UCMSCs dramatically improved the patients’ conditions with no adverse effects and no evidence of cancer recurrence throughout the trial period ([17, 18]). Moreover, UCMSCs treatment in active systemic lupus erythematosus (SLE) resulted in amelioration of the disease activity, serologic changes, and stabilization of proinflammatory cytokines in the patients [19]. The production of UCMSCs cells products from manufacturing methods must be tested for its safety prior to be used as therapeutic agents in cell therapy ([20]). Therefore, this Phase 1 clinical study was conducted to establish a new UCMSCs cell line (CLV-100) by assessing the safety and efficacy of intravenous allogeneic infusion of our manufactured UCMSCs (CLV-100) among healthy volunteers. This study also sought to compare the immunomodulatory effect of different dosage of CLV-100 between high-dose and low-dose infusion in healthy volunteers based on several clinical assessments and measurements of changes in systemic biomarkers. The findings of this study will act as a guideline and benchmark for future CLV-100 clinical research. 2. Materials and Methods 2.1. Study Design This is an open-label nonrandomized Phase 1 study assessing the safety and efficacy of CLV-100 infusion among 11 healthy subjects recruited at NSCMH Medical Centre in Seremban, Malaysia. The subjects were divided into 2 groups; low-dose group received 65 million cells (equivalent to about 1 million cells per kg body weight) (LD, ), while high dose group received 130 million cells (equivalent to about 2 million cells per kg body weight) (HD, ) of allogeneic infusion of CLV-100. This study was approved by the Medical Research and Ethics Committee (MREC) Ministry of Health Malaysia (NMRR-13-1152-17400) and monitored by independent Data Safety and Monitoring Board (DSMB). All subjects provided written informed consent before participating in the study. The inclusion and exclusion criteria were listed in Table 1. Key inclusion criteria (i) Men and women aged 40 years and older (ii) Subjects with normoglycemia (iii) Subjects with normotension (iv) Subjects with normal fasting lipid profile (v) Subject must understand patient information sheet and signed informed consent form Key exclusion criteria (i) Subject who has enrolled in another investigational drug trial or innovative therapeutics product-related trial or has completed the aforesaid within 3 months (ii) Subject with history of current or past use (within 1 year) of alcohol, smoking, or drug abuse (iii) Pregnant or nursing women (iv) Subject with known documented drug allergies (v) Subject who is required of the following medicines on a regular basis: anti-histamine, steroid, antibiotic, anti-inflammatory, immunosuppressant, and pain killer medications (vi) Subject who is currently on any hormone replacement or hormone suppressive therapy for any indication (vii) Subject with any acute or chronic infections or communicable diseases including hepatitis B, hepatitis C, or HIV (viii) Subject with any active or past history of neoplasia and primary hematological disease (ix) Subject with any renal impairment indicated by serum creatinine ≥120 μmol or creatinine clearance <60 mL/min (x) Subject with any cardiovascular disease including documented coronary disease of more than 50% stenosis, angina, myocardial infarction, heart failure, stroke, transient ischemic attack, and/or peripheral artery disease (xi) Subject with any diabetes mellitus (xii) Subject with any liver impairment indicated by serum aspartate transaminase and alanine transaminase greater than 1.5 times upper limit normal (xiii) Subject with any chronic pulmonary or airways disease (xiv) Subject with any current or past history of mental illness or cognitive impairment.

Efficacy of mesenchymal stem cells therapy on glucose levels in type 2 diabetes mellitus: A systematic review and meta-Analysis

Article

Full-text available

Oct 2020

Aims/introduction: In recent years, mesenchymal cellular therapies have received much attention in treatment of diabetes. In this meta-analysis we aimed to evaluate the efficacy of mesenchymal stem cell therapy in type 2 diabetes mellitus . Materials and methods: A comprehensive literature search was performed using PubMed, Scopus, Web of Science, and Central databases. A total of 1721 articles were identified from which nine full-text clinical trials were qualified to enter the current meta-analysis. The assessment groups included patients with type 2 diabetes, and levels of C-peptide, HbA1c, and insulin dose were analyzed before and after mesenchymal stem cell infusion. Data analysis was done in STATA V11. and the Jaded Score Scale was applied for quality assessment. Results: Changes on levels of C-peptide after mesenchymal stem cell therapy were: SMD=0.20, 95% CI= -0.61 to 1.00, on HbA1c levels: SMD= -1.45, 95%CI= -2.10 to -0.79, and on insulin dose were: SMD= -1.40, 95% CI= -2.88 to 0.09. Conclusions: This meta-analysis of prospective studies showed associations between mesenchymal stem cell therapy and control of glucose level in patients with type 2 diabetes.

Advances in translational orthopaedic research with species-specific multipotent mesenchymal stromal cells derived from the umbilical cord

Article

Sep 2020

Compliance with current regulations for the development of innovative medicines require the testing of candidate therapies in relevant translational animal models prior to human use. This poses a great challenge when the drug is composed of cells, not only because of the living nature of the active ingredient but also due to its human origin, which can subsequently lead to a xenogeneic response in the animals. Although immunosuppression is a plausible solution, this is not suitable for large animals and may also influence the results of the study by altering mechanisms of action that are, in fact, poorly understood. For this reason, a number of procedures have been developed to isolate homologous species-specific cell types to address preclinical pharmacodynamics, pharmacokinetics and toxicology. In this work, we present and discuss advances in the methodologies for derivation of multipotent Mesenchymal Stromal Cells derived from the umbilical cord, in general, and Wharton's jelly, in particular, from medium to large animals of interest in orthopaedics research, as well as current and potential applications in studies addressing proof of concept and preclinical regulatory aspects.

Transplantation of human dental pulp stem cells in streptozotocin-induced diabetic rats

Article

Full-text available

May 2020

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic β-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 106 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic β-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous β-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost β-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.

Identifying the Therapeutic Significance of Mesenchymal Stem Cells

Article

Full-text available

May 2020

The pleiotropic behavior of mesenchymal stem cells (MSCs) has gained global attention due to their immense potential for immunosuppression and their therapeutic role in immune disorders. MSCs migrate towards inflamed microenvironments, produce anti-inflammatory cytokines and conceal themselves from the innate immune system. These signatures are the reason for the uprising in the sciences of cellular therapy in the last decades. Irrespective of their therapeutic role in immune disorders, some factors limit beneficial effects such as inconsistency of cell characteristics, erratic protocols, deviating dosages, and diverse transfusion patterns. Conclusive protocols for cell culture, differentiation, expansion, and cryopreservation of MSCs are of the utmost importance for a better understanding of MSCs in therapeutic applications. In this review, we address the immunomodulatory properties and immunosuppressive actions of MSCs. Also, we sum up the results of the enhancement, utilization, and therapeutic responses of MSCs in treating inflammatory diseases, metabolic disorders and diabetes.

Low-Dose Decitabine Assists Human Umbilical Cord-Derived Mesenchymal Stem Cells in Protecting β Cells via the Modulation of the Macrophage Phenotype in Type 2 Diabetic Mice

Article

Full-text available

Apr 2020

Background: Progressive β-cell dysfunction, a major characteristic of type 2 diabetes (T2D), is closely related to the infiltration of inflammatory macrophages within islets. Mesenchymal stem cells (MSCs) have been identified to alleviate β-cell dysfunction by modulating macrophage phenotype in T2D, but the restoration of β-cells by a single MSC infusion is relatively transient. Decitabine (DAC) has been reported to polarize macrophages towards the anti-inflammatory phenotype at low doses. We therefore investigated whether low-dose decitabine could enhance the antidiabetic effect of MSCs and further promote the restoration of β-cell function. Methods: We induced a T2D mice model by high-fat diets and streptozotocin (STZ) injection. Mice were divided into five groups: the normal group, the T2D group, the DAC group, the MSC group, and the MSC plus DAC group (MD group). We examined the blood glucose and serum insulin levels of mice 1, 2, and 4 weeks after MSC and/or DAC treatment. Dynamic changes in islets and the phenotype of intraislet macrophages were detected via immunofluorescence. In vitro, we explored the effect of MSCs and DAC on macrophage polarization. Results: The blood glucose and serum insulin levels revealed that DAC prolonged the antidiabetic effect of MSCs to 4 weeks in T2D mice. Immunofluorescence staining demonstrated more sustainable morphological and structural amelioration in islets of the MD group than in the MSC group. Interestingly, further analysis showed more alternatively activated macrophages (M2, anti-inflammatory) and fewer classically activated macrophages (M1, proinflammatory) in islets of the MD group 4 weeks after treatment. An in vitro study demonstrated that DAC together with MSCs further polarized macrophages from the M1 to M2 phenotype via the PI3K/AKT pathway. Conclusion: These data unveiled that DAC prolonged the antidiabetic effect of MSCs and promoted sustainable β-cell restoration, possibly by modulating the macrophage phenotype. Our results offer a preferable therapeutic strategy for T2D.

Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies

Article

Full-text available

Mar 2020
INT J MOL SCI

Diabetes is a metabolic disease which affects not only glucose metabolism but also lipid and protein metabolism. It encompasses two major types: type 1 and 2 diabetes. Despite the different etiologies of type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively), the defining features of the two forms are insulin deficiency and resistance, respectively. Stem cell therapy is an efficient method for the treatment of diabetes, which can be achieved by differentiating pancreatic β-like cells. The consistent generation of glucose-responsive insulin releasing cells remains challenging. In this review article, we present basic concepts of pancreatic organogenesis, which intermittently provides a basis for engineering differentiation procedures, mainly based on the use of small molecules. Small molecules are more auspicious than any other growth factors, as they have unique, valuable properties like cell-permeability, as well as a nonimmunogenic nature; furthermore, they offer immense benefits in terms of generating efficient functional beta-like cells. We also summarize advances in the generation of stem cell-derived pancreatic cell lineages, especially endocrine β-like cells or islet organoids. The successful induction of stem cells depends on the quantity and quality of available stem cells and the efficient use of small molecules.

Therapeutic Potential of Wharton’s Jelly Mesenchymal Stem Cells for Diabetes: Achievements and Challenges

Article

Full-text available

Jan 2020

Diabetes mellitus (DM) is an alarming metabolic disease in which insulin secreting β-cells are damaged to various extent. Unfortunately, although currently available treatments help to manage the disease, however, patients usually develop complications, as well as decreased life quality and increased mortality. Thus, efficient therapeutic interventions to treat diabetes are urgently warranted. During the past years, mesenchymal stem cells (MSCs) have made their mark as a potential weapon in various regenerative medicine applications. The main fascination about MSCs lies in their potential to exert reparative effects on an amazingly wide spectrum of tissue injury. This is further reinforced by their ease of isolation and large ex vivo expansion capacity, as well as demonstrated multipotency and immunomodulatory activities. Among all the sources of MSCs, those isolated from umbilical cord-Wharton’s jelly (WJ-MSCs), have been proved to provide a great source of MSCs. WJ-MSCs do not impose any ethical concerns as those which exist regarding ESCs, and represent a readily available non-invasive source, and hence suggested to become the new gold standard for MSC-based therapies. In the current review, we shall overview achievements, as well as challenges/hurdles which are standing in the way to utilize WJ-MSCs as a novel efficient therapeutic modality for DM.

A bovine milk-derived peptide ameliorates pancreatic β-cell dedifferentiation through PI3K/Akt/FOXO1 signaling in type 2 diabetes

Article

Aug 2023

The lacto-ghrestatin derived nonapeptide (LGP9), a bioactive peptide derived from lacto-ghrestatin in bovine milk with the sequence of LIVTQTMKG, was investigated to determine its effects on islet β-cell dedifferentiation and associated mechanisms in type 2 diabetes mellitus (T2DM). On the animal level, type-2-diabetic (T2D) mice were generated by high-fat-diet (HFD) and streptozocin (STZ). LGP9 was given to T2D mice for four weeks at doses of 1 mg kg-1, 3 mg kg-1, and 9 mg kg-1. A variety of techniques (immunohistochemistry, western blot, QPCR, and ELISA) were employed to evaluate the impact of LGP9 on the diabetic injury. On the cellular level, the pancreatic cell lines, Rin-m5f cells and Min6 cells, were treated with high-glucose (HG) and high-glucose-high-lipid (HG/PA), respectively. The cell models were established to investigate the mechanism of LGP9 treatment on the islet β-cell dedifferentiation. For the mechanism study, the PI3K/Akt/FOXO1 pathway was investigated by inhibiting FOXO1 with its inhibitor and siRNA. Results showed that LGP9 improved the β-cell dedifferentiation, prevented the EMT process, and upregulated the PI3K/Akt/FOXO1 signaling in the pancreas of T2D mice. In addition, LGP9 promoted the structural and functional recovery of pancreatic islets and shielded the liver tissue in T2D mice. From the cellular level data, LGP9 prevented β-cell dedifferentiation and EMT occurrence. To a certain extent, the inhibition of FOXO1 restored PI3K/Akt/FOXO1 pathway activation and prevented β-cell dedifferentiation. In conclusion, these findings suggest that LGP9 ameliorated pancreatic β-cell dedifferentiation via PI3k/Akt/FOXO1 signaling in vivo and in vitro.

Effect of lawsone‐preconditioned mesenchymal stem cells on the regeneration of pancreatic β cells in Type 1 diabetic rats

Article

Jul 2023
CELL BIOCHEM FUNCT

Diabetes is one of the major health issues globally. Type 1 diabetes mellitus develops due to the destruction of pancreatic β cells. Mesenchymal stem cells (MSCs) having remarkable self‐renewal and differentiation potential, can regenerate β cells. MSCs preconditioned with bioactive small molecules possess enhanced biological features and therapeutic potential under in vivo environment. Interestingly, compounds of naphthoquinone class possess antidiabetic and anti‐inflammatory properties, and can be explored as potential candidates for preconditioning MSCs. This study analyzed the effect of lawsone‐preconditioned human umbilical cord MSCs (hUMSCs) on the regeneration of β cells in the streptozotocin (STZ)‐induced Type 1 diabetes (T1D) rats. hUMSCs were isolated and characterized for the presence of surface markers. MSCs were preconditioned with optimized concentration of lawsone. T1D rat model was established by injecting 50 mg/kg of STZ intraperitoneally. Untreated and lawsone‐preconditioned hUMSCs were transplanted into the diabetic rats via tail vein. Fasting blood sugar and body weight were monitored regularly for 4 weeks. Pancreas was harvested and β cell regeneration was evaluated by hematoxylin and eosin staining, and gene expression analysis. Immunohistochemistry was also done to assess the insulin expression. Lawsonepreconditioned hUMSCs showed better anti‐hyperglycemic effect in comparison with untreated hUMSCs. Histological analysis presented the regeneration of islets of Langerhans with upregulated expression of βcell genes and reduced expression of inflammatory markers. Immunohistochemistry revealed strong insulin expression in the preconditioned hUMSCs compared with the untreated hUMSCs. It is concluded from the present study that lawsone‐preconditioned hMSCs were able to exhibit pronounced anti‐hyperglycemic effect in vivo compared with hUMSCs alone.

The Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of Type 2 Diabetes- A Literature Review

Article

Full-text available

Mar 2023

Introduction: Type 2 diabetes (T2D) is the most common type of diabetes, affecting 6.28% of the population worldwide. Over the decades, multiple therapies and drugs have been developed to control T2D, but they are far from a long-term solution. Stem cells are promising as novel regenerative treatments, especially mesenchymal stem cells (MSCs), which are highly versatile in their regenerative and paracrine capabilities and characteristics. This makes them the most commonly used adult stem cells and ideal candidates to treat diabetes. Objective: To assess the safety and efficacy of mesenchymal stem cells (MSCs) in treating Type 2 diabetes (T2D) in humans. Methods: Mesenchymal stem cell-based treatments were studied in 262 patients. A total of 6 out of 58 trials fit our inclusion criteria in the last five years. Results: The treatment of patients with MSCs reduced the dosage of anti-diabetic drugs analyzed over a follow-up period of 12 months. The effective therapy dosage ranged from 1×106 cells/kg to 3.7×106 cells/kg. After treatment, HbAc1 levels were reduced by an average of 32%, and the fasting blood glucose levels were reduced to an average of 45%. The C-peptide levels were decreased by an average of 38% in 2 trials and increased by 36% in 4 trials. No severe adverse events were noted in all trials. Conclusion: This analysis concludes that MSC treatment of type 2 diabetes is safe and effective. A larger sample size is required, and the trials should also study the effect of differentiated MSCs as insulin-producing cells.

Лікування гіперліпідемії та інших метаболічних порушень біоактивними препаратами бергамоту і фолатів.

Article

Full-text available

Dec 2022

Treatment of hyperlipidemia and other metabolic disorders with bioactive preparations of bergamot and folates. Abstract. Citrus fruits are rich in polyphenols, and their use has long been associated with improving human health in hyperlipidemia, immune response disorders, coronary heart disease, and heart failure. Bergamot differs from other citrus fruits in the unique profile of flavonoids and glycosides present in its juice. It was shown that the flavonoid fraction of bergamot can reduce the level of lipids in the blood serum, improving the course of atherosclerosis due to the modulation of enzymatic activity, antioxidant, anti-inflammatory mechanisms, inhibition of activation and proliferation of monocytes. Clinical studies of the hypolipidemic properties of bergamot show that bergamot-derived polyphenols can lower low-density lipoprotein cholesterol, triglycerides, leptin, high-sensitivity C-reactive protein, and tumor necrosis factor alpha. The use of bergamot with low-dose statins led to an improvement in the lipid profile, suggesting a synergistic effect between statins and bergamot. Dietary polyphenols exhibit a number of important biological functions, including protection against atherosclerosis, oxidative stress, and degenerative diseases. Most of the biological functions of bergamot flavonoids are related to their antioxidant properties, which justifies the optimal use of flavonoids as alternative agents for the treatment of hyperlipidemia and cardiovascular complications. Folic acid (vitamin B9 ) is a known antioxidant compound, but derivatives of this vitamin, such as tetrahydrofolate, have higher antioxidant activity. However, the efficiency of enzymatic conversion of folic acid into its active forms in humans is very low. This vitamin plays an essential role in carbon metabolism, nucleic acid synthesis and DNA methylation. Significant positive effect of 5-methyltetrahydrofolate (MTHF) on type 2 diabetes and diabetopathies, metabolic syndrome, Alzheimer’s disease, and longterm effects of SARS-CoV-2 have been noted. MTHF effectively reduces the level of homocysteine that helps restore the function of the endothelium and reduce the risk of cardiovascular diseases. Therefore, the use of these compounds, both alone and in combination with other lipid-lowering drugs, is a promising strategy for the treatment of many serious diseases. Keywords: bergamot extracts; polyphenols; folic acid; hyperlipidemia; diabetes; atherosclerosis

Clinical efficacy of stem-cell therapy on diabetes mellitus: A systematic review and meta-analysis

Article

Nov 2022
TRANSPL IMMUNOL

Objective This systematic literature review aims to compare the efficacy and safety of traditional and stem cell (SC) therapies for type 1 (T1DM) and type 2 (T2DM) diabetes mellitus patients. Methods The PubMed, SciELO, BVS, and Medline databases were searched, and 38 original articles were selected, which included 647 control cases and 654 treatments with three-, six- and twelve-month follow-ups of T1DM and T2DM patients. The efficacy of stem cell therapy was validated by comparing laboratory parameters such as fasting blood glucose and C-peptide levels before and after treatment. The REML model was chosen for random effects, and the inverse of variance was used for fixed effects. The statistical analysis was carried out using Bioestat 5.0 and STATA 16.0 software. Results All SC treatments significantly reduced the need for insulin following six and twelve months of treatment, whereas there was no significant decrease after three months. Fasting blood glucose and glycosylated hemoglobin levels were significantly reduced in all follow-ups with SC. In addition, SC treatment caused a significant increase in C-peptide levels. Bone marrow hematopoietic stem cell therapy produced better results than the conventional drug treatment for diabetes mellitus (semagglutide). Conclusion The results with SC were significantly better, regardless of the follow-up period. Studies have proven cell therapy to be beneficial, safe, and effective.

Type 2 Diabetes Mellitus and Stem Cell Therapy: A Review

Article

Oct 2017

Most public health statistics outline the rapidly exploding burden of Type 2 diabetes mellitus as a chronic endemic disease related to sedentary lifestyle and obesity. Tremendous efforts and resources are being invested in finding new medical treatments and alternative therapies through cell-based replacement strategies among other methods. Several types of cells continue to be under active research, including autologous islet cells, allogeneic cadaveric islet cells, embryonic and induced pluripotent stem cells, bone marrow-derived hematopoietic and mononuclear cells, and mesenchymal stem cells of different sources. The objective of this review is to bring the reader up to speed on the efforts being spent in this field with a clear and critical approach to the difficult and sometimes futile methodology undermining the results obtained.

Effectiveness and safety of human umbilical cord-mesenchymal stem cells for treating type 2 diabetes mellitus

Article

Full-text available

Oct 2022

Background: Progressive pancreatic β-cell dysfunction is a fundamental part of the pathology of type 2 diabetes mellitus (T2DM). Cellular therapies offer novel opportunities for the treatment of T2DM to improve the function of islet β-cells. Aim: To evaluate the effectiveness and safety of human umbilical cord-mesenchymal stem cell (hUC-MSC) infusion in T2DM treatment. Methods: Sixteen patients were enrolled and received 1 × 106 cells/kg per week for 3 wk as intravenous hUC-MSC infusion. The effectiveness was evaluated by assessing fasting blood glucose, C-peptide, normal glycosylated hemoglobin A1c (HbA1c), insulin resistance index (homeostatic model assessment for insulin resistance), and islet β-cell function (homeostasis model assessment of β-cell function). The dosage of hypoglycemic agents and safety were evaluated by monitoring the occurrence of any adverse events (AEs). Results: During the entire intervention period, the fasting plasma glucose level was significantly reduced [baseline: 9.3400 (8.3575, 11.7725), day 14 ± 3: 6.5200 (5.2200, 8.6900); P < 0.01]. The HbA1c level was significantly reduced on day 84 ± 3 [baseline: 7.8000 (7.5250, 8.6750), day 84 ± 3: 7.150 (6.600, 7.925); P < 0.01]. The patients' islet β-cell function was significantly improved on day 28 ± 3 of intervention [baseline: 29.90 (16.43, 37.40), day 28 ± 3: 40.97 (19.27, 56.36); P < 0.01]. The dosage of hypoglycemic agents was reduced in all patients, of whom 6 (50%) had a decrement of more than 50% and 1 (6.25%) discontinued the hypoglycemic agents. Four patients had transient fever, which occurred within 24 h after the second or third infusion. One patient (2.08%) had asymptomatic nocturnal hypoglycemia after infusion on day 28 ± 3. No liver damage or other side effects were reported. Conclusion: The results of this study suggest that hUC-MSC infusion can improve glycemia, restore islet β-cell function, and reduce the dosage of hypoglycemic agents without serious AEs. Thus, hUC-MSC infusion may be a novel option for the treatment of T2DM.

Mesenchymal Stem Cells (MSCs): A Novel Therapy for Type 2 Diabetes

Article

Full-text available

Aug 2022

Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.

A Comparison of Mesenchymal Stem Cell Lineages for Treatment of Diabetes Mellitus

Article

Jan 2022

Diabetes Mellitus (DM) is a disease with increasing incidence rates and global awareness. Both type 1 (T1D) and type 2 (T2D) diabetes are classifications that require lifetime management. The dysfunction of β islet cells is a primary complication that requires treatment and may lead to several life-threatening complications including blindness, heart disease, and kidney failure. Mesenchymal stem cells (MSCs) are well known for their tissue regenerative action and have shown promising results for restoring β islet cell function as well as ameliorating sequelae of DM. There are several subtypes of MSCs, and each subtype is accompanied by a unique array of pros and cons. This review highlights 3 lineages of MSCs—bone marrow MSCs, adipose-derived (ADSCs), and umbilical cord (UBC-MSCs) - and summarizes the current feasibility and efficacy of each. On evaluation, current primary literature sources suggest that umbilical cord MSCs appear to have the most potential, with particular future implications for exosome research.

HYPERGLYCEMIA REVERSAL IN DIABETIC INFARCTED RAT POSTINTRAVENOUS INFUSION OF HUMAN MESENCHYMAL STEM CELLS

Article

Dec 2021

INTRODUCTION Hyperglycemia reversal and preservation/restoration of β-cells function in diabetic infarction remains as an attractive and challengeable therapeutic target. Mesenchymal stem cells (MSCs) are multipotent cells with a strong immunoregulatory potential that have emerged as a possible cell-based therapy for a variety of immunological diseases. The objective of this study was to examine the dose-dependent efcacy of intravenous administration of human umbilical cord blood derived MSCs (UCB-MSCs) in chemically induced rats with diabetic infraction. METHODS Wister rats (weight: 200-250g, males) received intraperitoneal streptozotocin injection followed by isoproterenol to develop diabetes infarction condition. After model development animals received intravenous single or double dose of human 6 UCB-MSCs (5 X 10 cells per animal at each dose) and followed up to 30 days post-administration. Pancreatic tissue histology, blood glucose and insulin levels were measured, and proportion of animal survival was calculated using Kaplan-Meier curve analysis. RESULTS Double dose of MSCs infusion resulted in reorganization of islet cells and partial restoration of β-cells at day 30. Comparatively faster restoration of glucose and insulin normalization was observed for two MSCs doses compared to single dose. Highest proportion of animal survival was observed (>85%) for double doses of MSCs infusion compared to single dose (>70%) at day 30. CONCLUSION Two consecutive intravenous doses of human UCB-MSCs can improve structural and functional decits of pancreatic tissues and maintain blood glucose and insulin levels in diabetic infarcted rats up to 30 days. However, identication of long-term effects entails longer follow-up periods, and larger sample sizes with other investigations.

Stem cell therapies in diabetes

Chapter

Jan 2022

Insulin insufficiency is a common problem for both type 1 and type 2 diabetes. While pancreas and islet transplantation emerged as a potential treatment in type 1 diabetes, insubstantial long-term outcomes and the limitations in donor tissue availability, quality, and distribution prompt scientists for alternative sources. Stem cell therapy is a promising alternative approach. Following the discovery of reprogramming of somatic cells into inducible human pluripotent stem cells, many studies focused on the differentiation protocols and quality control steps to generate differentiated end-stage cells that are safe, functional, and at a scale sufficient to replace damaged cells. This chapter focuses on the role of stem cells and their applications in diabetes.

The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy

Article

Full-text available

Jun 2021

Diabetic nephropathy (DN) is one of the most common diabetes mellitus (DM) microvascular complications, which always ends with end-stage renal disease (ESRD). Up to now, as the treatment of DN in clinic is still complicated, ESRD has become the main cause of death in diabetic patients. Mesenchymal stem cells (MSCs), with multi-differentiation potential and paracrine function, have attracted considerable attention in cell therapy recently. Increasing studies concerning the mechanisms and therapeutic effect of MSCs in DN emerged. This review summarizes several mechanisms of MSCs, especially MSCs derived exosomes in DN therapy, including hyperglycemia regulation, anti-inflammatory, anti-fibrosis, pro-angiogenesis, and renal function protection. We also emphasize the limitation of MSCs application in the clinic and the enhanced therapeutic role of pre-treated MSCs in the DN therapy. This review provides balanced and impartial views for MSC therapy as a promising strategy in diabetic kidney disease amelioration.

Human umbilical cord mesenchymal stem cells in type 2 diabetes mellitus: the emerging therapeutic approach

Article

Full-text available

May 2021
CELL TISSUE RES

The umbilical cord has been proved to be an easy-access, reliable, and useful source of mesenchymal stem cells (MSC) for clinical applications due to its primitive, immunomodulatory, non-immunogenic, secretory and paracrine, migratory, proliferative, and multipotent properties. This set of characteristics has recently attracted great research interest in the fields of nanotechnology and regenerative medicine and cellular therapy. Accumulating evidence supports a pronounced therapeutic potential of MSC in many different pathologies, from hematology to immunology, wound-healing, tissue regeneration, and oncology. Diabetes mellitus, branded the epidemic of the century, is considered a chronic metabolic disorder, representing a major burden for health system sustainability and an important public health challenge to modern societies. The available treatments for type 2 diabetes mellitus (T2DM) still rely mainly on combinations of oral antidiabetic agents with lifestyle and nutritional adjustments. Despite the continuous development of novel and better hypoglycemic drugs, their efficacy is limited in the installment and progression of silent T2DM complications. T2DM comorbidities and mortality rates still make it a serious, common, costly, and long-term manageable disease. Recently, experimental models, preclinical observations, and clinical studies have provided some insights and preliminary promising results using umbilical cord MSCs to treat and manage diabetes. This review focuses on the latest research and applications of human-derived umbilical cord MSC in the treatment and management of T2DM, exploring and systematizing the key effects of both umbilical cord MSC and its factor-rich secretome accordingly with the major complications associated to T2DM.

Biotecnología y sus aplicaciones en el sector salud

Book

Full-text available

Jan 2020

El libro se encuentra distribuido en tres grandes capítulos, el primero de ellos relacionado con aspectos básicos como la clasificación de la Biotecnología, el estudio de las fermentaciones microbianas, las enzimas y sus métodos de purificación, el estudio de los ácidos nucleicos y de las células madre. En el segundo capítulo, nos hemos enfocado en las herramientas de la Biotecnología como los procesos de inmovilización de enzimas, la producción de proteínas recombinantes y el estudio de los péptidos bioactivos. Finalmente, en el capítulo tres, nos enfocamos en las aplicaciones de la Biotecnología Roja o Médica, como las herramientas biotecnológicas para la producción de vacunas, las aplicaciones clínicas de las células madre, la aplicación clínica de los biomateriales, aplicaciones de la metagenómica y la metabolómica, finalizando con la importancia del estudio de las plantas medicinales en general y la actividad biológica de plantas del género Tabebuia, que ha sido ampliamente estudiada ...

Reversion of early- and late-stage β-cell dedifferentiation by human umbilical cord-derived mesenchymal stem cells in type 2 diabetic mice

Article

Mar 2021

Background aims The authors aimed to observe β-cell dedifferentiation in type 2 diabetes mellitus (T2DM) and investigate the reversal effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on early- and late-stage β-cell dedifferentiation. Methods In high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mice, the authors examined the predominant role of β-cell dedifferentiation over apoptosis in the development of T2DM and observed the reversion of β-cell dedifferentiation by UC-MSCs. Next, the authors used db/db mice to observe the progress of β-cell dedifferentiation from early to late stage, after which UC-MSC infusions of the same amount were performed in the early and late stages of dedifferentiation. Improvement in metabolic indices and restoration of β-cell dedifferentiation markers were examined. Results In HFD/STZ-induced T2DM mice, the proportion of β-cell dedifferentiation was much greater than that of apoptosis, demonstrating that β-cell dedifferentiation was the predominant contributor to T2DM. UC-MSC infusions significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In db/db mice, UC-MSC infusions in the early stage significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In the late stage, UC-MSC infusions mildly improved glucose homeostasis and partially reversed β-cell dedifferentiation. Combining with other studies, the authors found that the reversal effect of UC-MSCs on β-cell dedifferentiation relied on the simultaneous relief of glucose and lipid metabolic disorders. Conclusions UC-MSC therapy is a promising strategy for reversing β-cell dedifferentiation in T2DM, and the reversal effect is greater in the early stage than in the late stage of β-cell dedifferentiation.

Embryonic and Pluripotent Stem Cells

Chapter

Nov 2020

This chapter will focus on pluripotency as a key feature in determining the differentiation potential of cells and the importance of embryonic and pluripotent stem cells in research together with their promising applications in regenerative medicine. It also includes a brief description of the major findings on embryonic stem cells’ derivation, characterization, and differentiation. The differences between naïve and primed pluripotency will be highlighted, and the in vitro growth conditions contributing to these differences. This chapter will also cover major findings in nuclear reprogramming and the recent developments in induced pluripotent stem cell technology. Finally, we will conclude with the limitations of embryonic stem cells in clinical applications and areas for future research.

Hematopoietic Stem Cells and Control of Hematopoiesis

Chapter

Nov 2020

This chapter provides an overview of the origin and history of hematopoietic stem cells (HSCs) and the evolvement of their concept and hematopoiesis. It also illustrates the fate of hematopoietic cells arising from the mesoderm, and that later develops into the adult blood lineages by highlighting the major differences between primitive and definitive hematopoiesis. The chapter also includes a brief description of major findings of HSCs’ derivation, regulation, characterization, and differentiation. This chapter concludes with the current and future therapeutic potential of HSCs, and the barriers to their use for the development of new and improved therapies.

Introduction and Basic Concepts in Stem Cell Research and Therapy: The Facts and the Hype

Chapter

Nov 2020

Stem cells play critical roles in biological processes, such as tissue development and homeostasis; they also present great promise toward promoting breakthroughs in regenerative medicine. Stem cells may be used to explore disease modeling, for screening of new drugs, and for the treatment of intractable diseases. The transition of stem cell biology from basic research to clinical applications has involved both hope and hype. Indeed, premature application of stem cell therapy as a clinical “cure-all” without sufficient experimental, preclinical, or clinical research has led to shady practices and false promises. While this is, understandably, fueled by patients in need of cures for unmanageable chronic and degenerative diseases, hype-based practices have promoted the spread of clinically unproven therapies. These therapies may have no impact on the disease process or may result in devastating outcomes. Stem cells may ultimately have the capacity to treat intractable diseases, including diabetes, cardiovascular disorders, metabolic disorders, hematopoietic disorders, and immunodeficiency disorders. However, and despite significant promise, there remains a need to elucidate numerous misunderstandings associated with stem cell therapy and to define the current barriers and obstacles faced by those involved in stem cell research and its therapeutic applications. As such, the main goal of this chapter was to provide the reader with an overview of basic concepts in stem cell research and review the facts and the unfortunate hype with respect to current clinical applications and disease treatments.

Stem Cell Applications in Metabolic Disorders: Diabetes Mellitus

Chapter

Nov 2020

In this chapter we will discuss the definition of the metabolic disorders and the role of stem cells in their treatment. We will review the pathogenesis and current treatment of diabetes mellitus as an example of metabolic disorders. We will examine the regenerative therapy approaches to treat both Type I and Type II diabetes, and the different types of stem cells used for experimental transplantation and clinical trials. We will conclude with challenges in cell replacement therapy for diabetes, and new approaches to address these challenges.

VEGF/CDK2 are involved in diabetic organ regeneration

Article

Aug 2020
BIOCHEM BIOPH RES CO

Aim/Hypothesis: Diabetes is a hyperglycaemic disease treated by a set of allopathic drugs and natural biomolecules along with many variety of stem cell. We aim to investigate the role of these drugs in targeting common protein molecule in diabetes and its associated disease. We also aim to investigate the organ degeneration mechanistic pathway in diabetes. Method: We have generated diabetes using streptozotocin injection and treated them using bone marrow transplantation and curcumin administration. The organs were studied histopathologically and by immunofluorescence analysis while drugs were studied Pharmacogenomically. Result: Mice injected with streptozotocin have higher glucose and lower insulin, islet number/diameter, bone marrow cell number compared to control and bone marrow transplanted and curcumin administered mice. Histopathology staining demonstrates damaged morphology of pancreas, kidney, brain and cardiac muscle. Further, upon comparison of all allopathic and ayurvedic drugs used for diabetes several protein targets have been identified by reverse pharmacophore analysis using PharmMapper. VEGF, CDK2, insulin receptor, HSp90, eNOS, Fructose1,6 bisphosphatase, neprilysin, AchE, MAPK are several common protein targets of anti-diabetic drugs. Conclusion: This article demonstrates that VEGF and CDK2 are critical marker in organ damage in diabetes as well as organ regeneration.

Therapeutic Options for the Management of Postprandial Glucose in Patients With Type 2 Diabetes on Basal Insulin: FIGURE 1.

Article

Full-text available

Oct 2015
Clin Diabetes

Debbie Hinnen

In Brief For patients with type 2 diabetes who require add-on therapy to metformin plus basal insulin, GLP-1 receptor agonists may be a favorable option because they effectively manage postprandial glucose, reduce body weight, and have an overall favorable safety profile compared to other agents. Given the wide range of treatment combinations available for type 2 diabetes management, health professionals must partner with patients to determine the best choices based on patients' individual lifestyle, resources, and treatment goals.

IGF-1 enhances cell proliferation and survival during early differentiation of mesenchymal stem cells to neural progenitor-like cells

Article

Full-text available

Jul 2014
BMC NEUROSCI

Background There has been increasing interest recently in the plasticity of mesenchymal stem cells (MSCs) and their potential to differentiate into neural lineages. To unravel the roles and effects of different growth factors in the differentiation of MSCs into neural lineages, we have differentiated MSCs into neural lineages using different combinations of growth factors. Based on previous studies of the roles of insulin-like growth factor 1 (IGF-1) in neural stem cell isolation in the laboratory, we hypothesized that IGF-1 can enhance proliferation and reduce apoptosis in neural progenitor-like cells (NPCs) during differentiation of MSCs into NCPs. We induced MSCs differentiation under four different combinations of growth factors: (A) EGF + bFGF, (B) EGF + bFGF + IGF-1, (C) EGF + bFGF + LIF, (D) EGF + bFGF + BDNF, and (E) without growth factors, as a negative control. The neurospheres formed were characterized by immunofluorescence staining against nestin, and the expression was measured by flow cytometry. Cell proliferation and apoptosis were also studied by MTS and Annexin V assay, respectively, at three different time intervals (24 hr, 3 days, and 5 days). The neurospheres formed in the four groups were then terminally differentiated into neuron and glial cells. Results The four derived NPCs showed a significantly higher expression of nestin than was shown by the negative control. Among the groups treated with growth factors, NPCs treated with IGF-1 showed the highest expression of nestin. Furthermore, NPCs derived using IGF-1 exhibited the highest cell proliferation and cell survival among the treated groups. The NPCs derived from IGF-1 treatment also resulted in a better yield after the terminal differentiation into neurons and glial cells than that of the other treated groups. Conclusions Our results suggested that IGF-1 has a crucial role in the differentiation of MSCs into neuronal lineage by enhancing the proliferation and reducing the apoptosis in the NPCs. This information will be beneficial in the long run for improving both cell-based and cell-free therapy for neurodegenerative diseases.

A preliminary evaluation of efficacy and safety of Wharton’s jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus

Article

Full-text available

Apr 2014

Stem cell therapy has recently been introduced to treat patients with type 2 diabetes mellitus (T2DM). However, no data are available on the efficacy and safety of allogeneic Wharton's Jelly-derived mesenchymal stem cell (WJ-MSC) transplantation in patients with T2DM. Here we performed a non-placebo controlled prospective phase I/II study to determine efficacy and safety of WJ-MSC transplantation in T2DM. Twenty-two patients with T2DM were enrolled and received WJ-MSC transplantation through one intravenous injection and one intrapancreatic endovascular injection (catheterization). They were followed up for 12 months after transplantation. The primary endpoints were changes in the levels of glycated hemoglobin and C-peptide and the secondary endpoints included insulin dosage, fasting blood glucose (FBG), post-meal blood glucose (PBG), inflammatory markers and T lymphocyte counts. WJ-MSC transplantation significantly decreased the levels of glucose and glycated hemoglobin, improved C-peptide levels and beta cell function, and reduced markers of systemic inflammation and T lymphocyte counts. No major WJ-MSC transplantion-related adverse events occurred, but data suggest a temporary decrease in levels of C-peptide and beta cell function at one month after treatment, possibly related to intrapancreatic endovascular injection. Our data demonstrate that treatment with WJ-MSCs can improve metabolic control and beta cell function in patients with T2DM. The therapeutic mechanism may involve improvements in systemic inflammation and/or immunological regulation.Trial registration: Chinese Clinical Trial Register ChiCTR-ONC-10000985. Registered 23 September 2010.

Midkine, a Potential Link between Obesity and Insulin Resistance

Article

Full-text available

Feb 2014
PLOS ONE

Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK) is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone). In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3) pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.

Mesenchymal Stem Cells Use IDO to Regulate Immunity in Tumor Microenvironment

Article

Full-text available

Jan 2014
CANCER RES

Mesenchymal stem cells (MSCs) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment. Murine MSCs exert immunosuppressive effects through production of the nitric oxide synthase iNOS, while human MSCs utilize indoleamine 2,3-dioxygenase (IDO). Thus, studies of MSC-mediated immunomodulation in mice may not be informative in the setting of human disease, although this critical difference has been mainly ignored. To address this issue, we established a novel humanized system to model human MSCs, employing murine iNOS-/- MSCs that constitutively or inducibly express an ectopic human IDO gene . In this system, inducible IDO expression is driven by a mouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter. These IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T lymphocyte proliferation in vitro. In melanoma and lymphoma tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan. We found that MSC-IDO dramatically reduced both tumor-infiltrating CD8+ T cells and B cells. Our findings offer an important new line of evidence that interventional targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells themselves.

Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy The TAC-HFT Randomized Trial

Article

Full-text available

Nov 2013
J Am Med Assoc

Importance: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. Objective: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. Design, setting, and patients: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. Interventions: Injections in 10 LV sites with an infusion catheter. Main outcomes and measures: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. Results: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. Conclusions and relevance: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. Trial registration: clinicaltrials.gov Identifier: NCT00768066.

Effect of Progenitor Cell Mobilization With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Peripheral Artery Disease A Randomized Clinical Trial

Article

Full-text available

Nov 2013
J Am Med Assoc

Importance Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown.Objective To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication.Design, Setting, and Participants In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012.Interventions Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily.Main Outcomes and Measures The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores.Results Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, −6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, −0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, −0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups.Conclusions and Relevance Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication.Trial Registration clinicaltrials.gov Identifier: NCT01041417

Biological, Functional and Genetic Characterization of Bone Marrow-Derived Mesenchymal Stromal Cells Isolated From Pediatric Patients Affected by Acute Lymphoblastic Leukemia

Article

Full-text available

Aug 2013
PLOS ONE

Alterations in hematopoietic microenvironment of acute lymphoblastic leukemia patients have been claimed to occur, but little is known about the components of marrow stroma in these patients. In this study, we characterized mesenchymal stromal cells (MSCs) isolated from bone marrow (BM) of 45 pediatric patients with acute lymphoblastic leukemia (ALL-MSCs) at diagnosis (day+0) and during chemotherapy treatment (days: +15; +33; +78), the time points being chosen according to the schedule of BM aspirates required by the AIEOP-BFM ALL 2009 treatment protocol. Morphology, proliferative capacity, immunophenotype, differentiation potential, immunomodulatory properties and ability to support long-term hematopoiesis of ALL-MSCs were analysed and compared with those from 41 healthy donors (HD-MSCs). ALL-MSCs were also genetically characterized through array-CGH, conventional karyotyping and FISH analysis. Moreover, we compared ALL-MSCs generated at day+0 with those isolated during chemotherapy. Morphology, immunophenotype, differentiation potential and in vitro life-span did not differ between ALL-MSCs and HD-MSCs. ALL-MSCs showed significantly lower proliferative capacity (p<0.001) and ability to support in vitro hematopoiesis (p = 0.04) as compared with HD-MSCs, while they had similar capacity to inhibit in vitro mitogen-induced T-cell proliferation (p = N.S.). ALL-MSCs showed neither the typical translocations carried by the leukemic clone (when present), nor other genetic abnormalities acquired during ex vivo culture. Our findings indicate that ALL-MSCs display reduced ability to proliferate and to support long-term hematopoiesis in vitro. ALL-MSCs isolated at diagnosis do not differ from those obtained during treatment.

Exosomes Released by Islet-Derived Mesenchymal Stem Cells Trigger Autoimmune Responses in NOD Mice

Article

Full-text available

Oct 2013

Exosomes (EXOs) are secreted, nano-sized membrane vesicles that contain potent immunostimulatory materials. We have recently demonstrated that insulinoma-released EXOs can stimulate the autoimmune responses in non-obese diabetic (NOD) mice, a spontaneous disease model for type 1 diabetes (T1D). To investigate whether primary islet cells can produce EXOs, we isolated cells from the islet of Langerhans of NOD mice and cultured them in vitro. Interestingly, cultured islets release fibroblast-like, fast-replicating cells that express mesenchymal stem cell (MSC) markers including CD105 and Sca-1. These islet MSC-like cells (iMSC) release highly immunostimulatory EXOs that could activate autoreactive B and T cells endogenously primed in NOD mice. Serum exosome levels and EXO-induced IFN-γ production were positively correlated with disease progression at the early prediabetic stage. Consistent with these observations, immunohistological analysis of pancreata showed that CD105(+) cells are restricted to the peri-islet area in normal islets but penetrate into the β-cell area as lymphocyte infiltration occurs. Immunization with EXOs promoted expansion of transferred diabetogenic T cells and accelerated the effector T cell-mediated destruction of islets. Thus, EXOs could be the autoantigen carrier with potent adjuvant activities and may function as the autoimmune trigger in NOD mice.

Mesenchymal Stem Cells Alleviate Bacteria-Induced Liver Injury in Mice by Inducing Regulatory Dendritic Cells

Article

Full-text available

Feb 2014
HEPATOLOGY

Unlabelled: Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study we used Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4(+) T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC-treated mice. Intriguingly, a distinct liver population of CD11c(+) MHCII(hi) CD80(lo) CD86(lo) regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-β production. Further mechanistic studies demonstrated that MSC-derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c(+) B220(-) DC precursors into regulatory DCs in a phosphoinositide 3-kinase-dependent manner. Conclusion: MSCs induce regulatory DCs from CD11c(+) B220(-) DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and lays a foundation for application of MSCs in FHF therapy.

Targeting insulin resistance in type 2 diabetes via immune modulation of cord blood-derived multipotent stem cells (CB-SCs) in Stem Cell Educator therapy: phase I/II clinical trial

Article

Full-text available

Jul 2013
BMC MED

The prevalence of type 2 diabetes (T2D) is increasing worldwide and creating a significant burden on health systems, highlighting the need for the development of innovative therapeutic approaches to overcome immune dysfunction, which is likely a key factor in the development of insulin resistance in T2D. It suggests that immune modulation may be a useful tool in treating the disease. In an open-label, phase 1/phase 2 study, patients (N = 36) with long-standing T2D were divided into three groups (Group A, oral medications, n = 18; Group B, oral medications + insulin injections, n = 11; Group C having impaired beta-cell function with oral medications + insulin injections, n = 7). All patients received one treatment with the Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, briefly co-cultures them with adherent cord blood-derived multipotent stem cells (CB-SCs), and returns the educated autologous cells to the patient's circulation. Clinical findings indicate that T2D patients achieve improved metabolic control and reduced inflammation markers after receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C) in Group A and B was significantly reduced from 8.61% +/- 1.12 at baseline to 7.25% +/- 0.58 at 12 weeks (P = 2.62E-06), and 7.33% +/- 1.02 at one year post-treatment (P = 0.0002). Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that insulin sensitivity was improved post-treatment. Notably, the islet beta-cell function in Group C subjects was markedly recovered, as demonstrated by the restoration of C-peptide levels. Mechanistic studies revealed that Stem Cell Educator therapy reverses immune dysfunctions through immune modulation on monocytes and balancing Th1/Th2/Th3 cytokine production. Clinical data from the current phase 1/phase 2 study demonstrate that Stem Cell Educator therapy is a safe approach that produces lasting improvement in metabolic control for individuals with moderate or severe T2D who receive a single treatment. In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registrationClinicalTrials.gov number, NCT01415726.

Autologous Umbilical Cord Blood (UCB) Infusion Followed by Oral Docosahexanoic Acid (DHA) and Vitamin D (VitD) Supplementation for C-Peptide Preservation in Children with Type 1 Diabetes (T1D).

Article

Full-text available

Apr 2013

We sought to determine if autologous umbilical cord blood (UCB) infusion followed by 1 year of supplementation with vitamin D (Vit D) and docosoahexaenoic acid (DHA) can preserve C-peptide in children with type 1 diabetes (T1D). We conducted an open label, 2:1 randomized study in which 15 T1D subjects with stimulated C-peptide > 0.2 pmol/mL received either (1) autologous UCB infusion, one year of daily oral Vit D (2,000IU) and DHA (38mg/kg), and intensive diabetes management, or (2) intensive diabetes management alone. Primary analyses were performed 1 year following UCB infusion. Treated (n=10) and control (n=5) subjects had median ages of 7.2 and 6.6 years, respectively. No severe adverse events were observed. While the absolute rate of C-peptide decline was slower in treated versus control subjects, intergroup comparisons failed to reach significance (P=0.29). AUC C-peptide declined and insulin use increased in both groups (P=<0.01). VitD levels remained stable in treated subjects but declined in controls (P=0.01). DHA levels rose in treated subjects versus controls (P =0.003). CD4:CD8 ratio remained stable in treated subjects but declined in controls (P=0.03). No changes were seen in regulatory T cell frequency, total CD4 counts, or autoantibody titers. Autologous UCB infusion followed by daily supplementation with Vit D and DHA was safe but failed to preserve C-peptide. Lack of significance may reflect small sample size. Future efforts will require expansion of specific immunoregulatory cell subsets, optimization of combined immunoregulatory and anti-inflammatory agents, and larger study cohorts.

β-Cell Regeneration Mediated by Human Bone Marrow Mesenchymal Stem Cells

Article

Full-text available

Aug 2012
PLOS ONE

Bone marrow mesenchymal stem cells (BMSCs) have been shown to ameliorate diabetes in animal models. The mechanism, however, remains largely unknown. An unanswered question is whether BMSCs are able to differentiate into β-cells in vivo, or whether BMSCs are able to mediate recovery and/or regeneration of endogenous β-cells. Here we examined these questions by testing the ability of hBMSCs genetically modified to transiently express vascular endothelial growth factor (VEGF) or pancreatic-duodenal homeobox 1 (PDX1) to reverse diabetes and whether these cells were differentiated into β-cells or mediated recovery through alternative mechanisms. Human BMSCs expressing VEGF and PDX1 reversed hyperglycemia in more than half of the diabetic mice and induced overall improved survival and weight maintenance in all mice. Recovery was sustained only in the mice treated with hBMSCs-VEGF. However, de novo β-cell differentiation from human cells was observed in mice in both cases, treated with either hBMSCs-VEGF or hBMSCs- PDX1, confirmed by detectable level of serum human insulin. Sustained reversion of diabetes mediated by hBMSCs-VEGF was secondary to endogenous β-cell regeneration and correlated with activation of the insulin/IGF receptor signaling pathway involved in maintaining β-cell mass and function. Our study demonstrated the possible benefit of hBMSCs for the treatment of insulin-dependent diabetes and gives new insight into the mechanism of β-cell recovery after injury mediated by hBMSC therapy.

Immune Regulatory Properties of Allogeneic Adipose-Derived Mesenchymal Stem Cells in the Treatment of Experimental Autoimmune Diabetes

Article

Full-text available

Jun 2012

Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.

Infusion of Mesenchymal Stem Cells Ameliorates Hyperglycemia in Type 2 Diabetic Rats

Article

Full-text available

Jun 2012

Infusion of mesenchymal stem cells (MSCs) has been shown to effectively lower blood glucose in diabetic individuals, but the mechanism involved could not be adequately explained by their potential role in promoting islet regeneration. We therefore hypothesized that infused MSCs might also contribute to amelioration of the insulin resistance of peripheral insulin target tissues. To test the hypothesis, we induced a diabetic rat model by high-fat diet/streptozotocin (STZ) administration, performed MSC infusion during the early phase (7 days) or late phase (21 days) after STZ injection, and then evaluated the therapeutic effects of MSC infusion and explored the possible mechanisms involved. MSC infusion ameliorated hyperglycemia in rats with type 2 diabetes (T2D). Infusion of MSCs during the early phase not only promoted β-cell function but also ameliorated insulin resistance, whereas infusion in the late phase merely ameliorated insulin resistance. Infusion of MSCs resulted in an increase of GLUT4 expression and an elevation of phosphorylated insulin receptor substrate 1 (IRS-1) and Akt (protein kinase B) in insulin target tissues. This is the first report of MSC treatment improving insulin sensitivity in T2D. These data indicate that multiple roles and mechanisms are involved in the efficacy of MSCs in ameliorating hyperglycemia in T2D.

Multiple Intravenous Transplantations of Mesenchymal Stem Cells Effectively Restore Long-Term Blood Glucose Homeostasis by Hepatic Engraftment and β-Cell Differentiation in Streptozocin-Induced Diabetic Mice

Article

Full-text available

Oct 2011
CELL TRANSPLANT

Depletion of pancreatic β-cells results in insulin insufficiency and diabetes mellitus (DM). Single transplantation of mesenchymal stem cells exhibits short-term effects in some preclinical studies. Here, we further investigated the long-term therapeutic effects of multiple intravenous MSC transplantations. In this study, multiple human MSC transplantations (4.2 × 10(7) cells/kg each time) were performed intravenously at 2-week intervals into streptozocin (STZ)-induced diabetic mice for 6 months. Blood sugar, insulin, renal function, cholesterol, and triglyceride levels were monitored. We demonstrated that compared to single intravenous transplantation, which only transiently decreased hyperglycemia, multiple MSC transplantations effectively restored blood glucose homeostasis. Systemic oxidative stress levels were reduced from the seventh week of treatment. From the 11th week, production of human insulin was markedly increased. When MSC transplantation was skipped after blood sugar level returned to normal at the end of 15th week, a sharp rebound of blood sugar occurred, and was then controlled by subsequent transplantations. At the end of 6 months, histopathology examination revealed MSCs specifically engrafted into liver tissues of the recipients. Fifty-one percent of human cells in the recipient liver coexpressed human insulin, especially those surrounding the central veins. Taken together, intravenous MSC delivery was safe and effective for blood glucose stabilization in this preclinical DM model. Multiple transplantations were essential to restore and maintain glucose homeostasis through decreasing systemic oxidative stress in the early stage and insulin production in the late stage. Liver engraftment and differentiation into insulin-producing cells account for the long-term therapeutic effects of MSCs.

Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: A pilot study

Article

Full-text available

Mar 2011

Mesenchymal stem cells (MSC) have been used in clinical trials for severe diabetes, a chronic disease with high morbidity and mortality. Bone marrow is the traditional source of human MSC, but human term placenta appears to be an alternative and more readily available source. Here, the therapeutic effect of human placenta-derived MSC (PD-MSC) was studied in type 2 diabetes patients with longer duration, islet cell dysfunction, high insulin doses as well as poor glycemic control in order to evaluate the safety, efficacy and feasibility of PDMSC treatment in type 2 diabetes (T2D). Ten patients with T2D received three intravenous infusions of PDSC, with one month interval of infusion. The total number of PDSC for each patient was (1.22-1.51) × 10(6)/kg, with an average of 1.35 × 10(6)/kg. All of the patients were followed up after therapy for at least 3 months. A daily mean dose of insulin used in 10 patients was decreased from 63.7±18.7 to 34.7±13.4 IU (P<0.01), and the C-peptide level was increased from 4.1 ±3.7 ng/mL to 5.6 ±3.8 ng/mL (P<0.05) respectively after therapy. In 4 of 10 responders their insulin doses reduced more than 50% after infusion. The mean levels of insulin and C-peptide at each time point in a total of 10 patients was higher after treatment (P<0.05). No fever, chills, liver damage and other side effects were reported. The renal function and cardiac function were improved after infusion. The results obtained from this pilot clinical trial indicate that transplantation of PD-MSC represents a simple, safe and effective therapeutic approach for T2D patients with islet cell dysfunction. Further large-scale, randomized and well-controlled clinical studies will be required to substantiate these observations.

The Antidiabetic Effect of MSCs Is Not Impaired by Insulin Prophylaxis and Is Not Improved by a Second Dose of Cells

Article

Full-text available

Jan 2011
PLOS ONE

Type 1 diabetes mellitus (T1D) is due to autoimmune destruction of pancreatic beta-cells. Previously, we have shown that intravenously administered bone marrow-derived multipotent mesenchymal stromal cells (MSCs) allows pancreatic islet recovery, improves insulin secretion and reverts hyperglycemia in low doses streptozotocin (STZ)-induced diabetic mice. Here we evaluate whether insulin prophylaxis and the administration of a second dose of cells affect the antidiabetic therapeutic effect of MSC transplantation. Insulitis and subsequent elimination of pancreatic beta-cells was promoted in C57BL/6 mice by the injection of 40 mg/kg/day STZ for five days. Twenty-four days later, diabetic mice were distributed into experimental groups according to if they received or not insulin and/or one or two doses of healthy donor-derived MSCs. Three and half months later: glycemia, pancreatic islets number, insulinemia, glycated hemoglobin level and glucose tolerance were determined in animals that did not received exogenous insulin for the last 1.5 months. Also, we characterized MSCs isolated from mice healthy or diabetic. The therapeutic effect of MSC transplantation was observed in diabetic mice that received or not insulin prophylaxis. Improvements were similar irrespective if they received one or two doses of cells. Compared to MSCs from healthy mice, MSCs from diabetic mice had the same proliferation and adipogenic potentials, but were less abundant, with altered immunophenotype and no osteogenic potential. Our preclinical results should be taken into account when designing phase II clinical trials aimed to evaluate MSC transplantation in patients with T1D. Cells should be isolated form healthy donor, insulin prophylaxis could be maintained and a second dose, after an elapse of two months, appears unnecessary in the medium-term.

10 Biological, Functional and Genetic Characterization of Bone Marrow-Derived Mesenchymal Stromal Cells from Pediatric Patients Affected by Acute Lymphoblastic Leukemia

Data

May 2015

Clinical Neuropathy Scales in Neuropathy Associated with Impaired Glucose Tolerance

Article

Feb 2015
J DIABETES COMPLICAT

Disagreement exists on effective and sensitive outcome measures in neuropathy associated with impaired glucose tolerance (IGT). Nerve conduction studies and skin biopsies are costly, invasive and may have their problems with reproducibility and clinical applicability. A clinical measure of neuropathy that has sufficient sensitivity and correlates to invasive measures would enable significant future research. Data was collected prospectively on patients with IGT and symptomatic early neuropathy (neuropathy symptoms <2years) and normal controls. The seven scales that were examined were the Neuropathy Impairment Score of the Lower Limb (NIS-LL), Michigan Diabetic Neuropathy Score (MNDS), modified Toronto Clinical Neuropathy Scale (mTCNS), Total Neuropathy Score (Clinical) (TNSc), The Utah Early Neuropathy Scale (UENS), the Early Neuropathy Score (ENS), and the Neuropathy Disability Score (NDS). All seven clinical scales were determined to be excellent in discriminating between patients with neuropathy from controls without neuropathy. The strongest discrimination was seen with the mTCNS. The best sensitivity and specificity for the range of scores obtained, as determined by using receiver operating characteristic curves, was seen for the mTCNS followed by the TNSc. Most scales show a stronger correlation with measures of large rather than small fiber neuropathy. All seven scales identify patients with neuropathy. For the purpose of screening potential patients for a clinical study, the mTCNS followed by the TNSc would be most helpful to select patients with neuropathy. Published by Elsevier Inc.

Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of Multiple Sclerosis

Article

Jan 2015

Increased internalization of Staphylococcus aureus and cytokine expression in human Wharton's jelly mesenchymal stem cells

Article

Jun 2014

Background: Although a large number of studies have documented the interaction of mesenchymal stem cells (MSCs) with cells of both the innate and adaptive immune systems, not much is known about how bacteria interact with MSCs and how this might influence MSCs behavior. In this study, we investigated the impact of Staphylococcus aureus (S. aureus), on viability and cytokines' production of human Wharton's jelly-MSCs (WJ-MSCs). Objective: To investigate if WJ-MSCs: (1) internalize S. aureus; (2) are able to survive and (3) release immunomodulatory mediators after interaction with S. aureus. Methods: WJ-MSCs were exposed to S. aureus at a multiplicity of infection (MOI) of 10:1 or 30:1 for different designed times. After interaction, intracellular bacteria were quantified as well as MSCs viability. Expression and cytokine-secretion were assessed using quantitative real-time PCR and ELISA. Results: We found that the challenge of WJ-MSCs with S. aureus resulted in increased internalization of S. aureus in a time-dependent manner until six hours post-infection at either MOI of 10:1 and 30:1 and in increased expression of IL-6 mRNA and secretion of TNF-α at six hours and nine hours post-infection (p<0.05). Conclusions: These results indicate that WJ-MSCs are able to internalize S. aureus and reveal a potential important function of these cells in the immune response.

Efficacy and Safety of Sitagliptin for the Treatment of Nonalcoholic Fatty Liver Disease with Type 2 Diabetes Mellitus

Article

Mar 2014
HEPATO-GASTROENTEROL

Background/aims: Dipeptidyl peptidase-4 inhibitor is useful for the treatment of type 2 diabetes mellitus (DM). However, effects on liver function and glucose metabolism in nonalcoholic fatty liver disease (NAFLD) have not been established. The objective of this study was to evaluate the efficacy and safety of sitagliptin in NAFLD patients with type 2 DM. Methodology: Forty-four patients with biopsy-proven NAFLD with type 2 DM were evaluated. Patients were administered sitagliptin (50 mg/day) for 12 months. Results: Hemoglobin A1c (HbA1c) decreased by 0.7% after treatment (P < 0.001). While HbA1c levels decreased by 0.4% in the low HbA1c (< 7.5%) group, those decreased by 1.2% in the high HbAlc (> or = 7.5%) group. Liver transaminases did not change significantly during the treatment. Improvement of HbA1c (deltaHbA1c) and that of aspartate aminotransferase (deltaAST), alanine aminotransferase (deltaALT) was positively correlated (r = 0.425, and 0.455, respectively), especially in the high HbA1c (> or = 7.5%) group before treatment (r = 0.568, and 0.501, respectively). Conclusions: Sitagliptin for the treatment of NAFLD with type2 DM was safe and showed similar antidiabetic effects as reported for type 2 DM, suggesting that tight glycemic control would contribute to the improvement of NAFLD based from the findings of correlation between the changes of HbA1c and transaminases.

Effect and mechanisms of human Wharton’s jelly-derived mesenchymal stem cells on type 1 diabetes in NOD model

Article

Mar 2014
ENDOCRINE

Type 1 diabetes is an autoimmune disease that results from an inflammatory destruction of β-cells in islets. Mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs) own a peculiar immunomodulatory feature and might reverse the inflammatory destruction and repair the function of β-cells. Sixty NOD mice were divided into four groups, including normal control group, WJ-MSCs prevention group (before onset), WJ-MSCs treatment group (after onset), and diabetic control group. After homologous therapy, onset time of diabetes, levels of fasting plasma glucose (FPG), fed blood glucose and C-peptide, regulation of cytokines, and islet cells were examined and evaluated. After WJ-MSCs infusion, FPG and fed blood glucose in WJ-MSCs treatment group decreased to normal level in 6-8 days and maintained for 6 weeks. Level of fasting C-peptide of these mice was higher compared to diabetic control mice (P = 0.027). In WJ-MSCs prevention group, WJ-MSCs played a protective role for 8-week delayed onset of diabetes, and fasting C-peptide in this group was higher compared to the other two diabetic groups (P = 0.013, 0.035). Compared with diabetic control group, frequencies of CD4(+)CD25(+)Foxp3(+) Tregs in WJ-MSCs prevention group and treatment group were higher, while levels of IL-2, IFN-γ, and TNF-α were lower (P < 0.001); the degree of insulitis was also depressed, especially for WJ-MSCs prevention group(P < 0.05). Infusion of WJ-MSCs could aid in T1DM through regulation of the autoimmunity and recovery of islet β-cells no matter before or after onset of T1DM. WJ-MSCs might be an effective method for T1DM.

Classification of diabetic retinopathy and diabetic macular edema

Article

Dec 2013

The global incidence and prevalence of diabetes mellitus (DM) have reached epidemic proportions. Estimates indicate that more than 360 million people will be affected by DM by 2030. All of these individuals will be at risk of developing diabetic retinopathy (DR). It is extremely important to categorize, classify and stage the severity of DR in order to establish adequate therapy. With proper management more than 90% of cases of visual loss can be prevented. The purpose of the current paper is to review the classification of DR with a special emphasis on the International Clinical Disease Severity Scale for DR. This new classification is simple to use, easy to remember and based on scientific evidence. It does not require specialized examinations such as optical coherence tomography or fluorescein angiography. It is based on clinical examination and applying the Early Treatment of Diabetic Retinopathy Study 4:2:1 rule.

Immunosuppression does not affect human bone marrow mesenchymal stromal cell efficacy after transplantation in traumatized mice brain

Article