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CS–IGF-1C hydrogel exerts antiapoptotic effects in vitro. (A) ADSC survival upon exposure to H 2 O 2 was analyzed by BLI. ADSCs were cultured on CS–IGF-1C hydrogel–coated, CS hydrogel–coated, or noncoated plates and exposed to H 2 O 2 . (B) Quantification of BLI signals reveals that H 2 O 2 treatment resulted in dose-dependent apoptotic cell death and that CS–IGF-1C hydrogel ameliorated cell survival significantly . Data are expressed as mean6SEM. *P,0.05 versus noncoated; # P,0.05 versus CS. (C) Real-time RT-PCR analysis of apoptosis-related gene expression of ADSCs after treatment with 100 nM H 2 O 2 for 2 hours. The cells were cultured on CS–IGF-1C hydrogel–coated, CS hydrogel–coated, or noncoated plates for 1, 7, and 14 days. Data are expressed as mean6SEM. *P,0.05 versus noncoated; # P,0.05 versus CS. Experiments were performed in triplicate.
Source publication
Low cell retention and engraftment after transplantation limit the successful application of stem cell therapy for AKI. Engineered microenvironments consisting of a hydrogel matrix and growth factors have been increasingly successful in controlling stem cell fate by mimicking native stem cell niche components. Here, we synthesized a bioactive hydro...
Contexts in source publication
Context 1
... the present study, ADSCs were isolated from transgenic mice, which express firefly luciferase (Fluc) and green fluorescent pro- tein (GFP) (Supplemental Figure 2). Cell proliferation assay indicated that the opti- mal concentration of CS-IGF-1C hydrogel was 3% ( Figure 1E), and subsequent experiments revealed superior biocompat- ibility of CS-IGF-1C hydrogel (Supplemental Figure 3). ...
Context 2
... 2 O 2 treatment resulted in a dose- dependent decrease of BLI signal. When cells were cultured on CS hydrogel-coated plates, cell survival displayed a significant ame- lioration and CS-IGF-1C hydrogel further increased this effect ( Figure 2, A and B). To determine the pathway involved in this protective action, we measured the expression of apoptosis-related genes in ADSCs after treatment with H 2 O 2 (100 mM) for 2 hours. ...
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Poor cell viability after transplantation has restricted the therapeutic capacity of mesenchymal stem cells (MSCs) for cardiac dysfunction after myocardial infarction (MI). Growth arrest-specific gene 6 (Gas6) encodes a secreted γ-carboxyglutamic acid (Gla)-containing protein that functions in cell growth, adhesion, chemotaxis, mitogenesis and cell...
Citations
... The renal IRI models were established as previously reported [26]. Mice were anesthetized via intraperitoneal injection of 2.5% avertin (Sigma-Aldrich, Oakville, ON, Canada) at a dosage of 240 mg/kg. ...
Background
Acute kidney injury (AKI) is a common and severe clinical condition. However, the underlying mechanisms of AKI have not been fully elucidated, and effective treatment options remain limited. Studies have shown that immune cells play a critical role in AKI, with regulatory T cells (Tregs) being one of the most important immunosuppressive lymphocytes. Tregs proliferation can attenuate AKI, whereas depletion exacerbates kidney injury. Given that endothelial cells (ECs) are the initial cells that interact with immune cells when they invade the tissue parenchyma, ECs are closely associated with immune reactions.
Methods and results
In this study, P-selectin binding peptide-extracellular vesicles (PBP-EVs) that target and repair ECs are engineered. Transcriptome sequencing reveals that PBP-EVs reduce the expression of inflammatory genes in AKI mice. Using high-resolution intravital two-photon microscopy (TPM), an increased recruitment of Tregs in the kidneys of AKI Foxp3-EGFP transgenic mice following PBP-EVs treatment is observed, as well as significant Lgr5⁺ renal stem cell proliferation in AKI Lgr5-CreERT2; R26mTmG mice. Additionally, PBP-EVs treatment result in reduced infiltration of inflammatory cells, pathological damage and fibrosis of AKI mice. Upon depletion of Tregs in Foxp3-DTR transgenic mice, we observe diminished therapeutic effect of PBP-EVs on AKI.
Conclusions
The experimental results indicate that PBP-EVs can promote the repair and regeneration of AKI by mitigating endothelial cell damage and subsequently modulating Tregs and the immune microenvironment. These findings provide novel insights and strategies for the treatment of AKI.
... With the degradation of gelatinized hydrogels, the controlled release of cargo payloads such as drugs, cyclic peptides, NPs, and biovesicles plays a pivotal role in their therapeutic effects [72]. In addition to serving as drug-loaded carriers, hydrogels can serve as engineered matrices with growth factors to provide suitable conditions for the selfrenewal and differentiation of mesenchymal stem cells (MSCs) [73]. The therapeutic effect of EVs on kidney injury can be improved by encapsulation in thermosensitive injectable collagen hydrogels, which significantly increase the stability and long-term retention of EVs in vivo [74]. ...
Acute kidney injury (AKI), a common kidney disease in which renal function decreases rapidly due to various etiologic factors, is an important risk factor for chronic kidney disease (CKD). The pathogenesis of AKI leading to CKD is complex, and effective treatments are still lacking, which seriously affects the prognosis and quality of life of patients with kidney disease. Nanomedicine, a discipline at the intersection of medicine and nanotechnology, has emerged as a promising avenue for treating kidney diseases ranging from AKI to CKD. Increasing evidence has validated the therapeutic potential of nanomedicine in AKI; however, little attention has been paid to its effect on AKI for patients with CKD. In this review, we systematically emphasize the major pathophysiology of the AKI-to-CKD transition and summarize the treatment effects of nanomedicine on this transition. Furthermore, we discuss the key role of nanomedicine in the regulation of targeted drug delivery, inflammation, oxidative stress, ferroptosis, and apoptosis during the transition from AKI to CKD. Additionally, this review demonstrates that the integration of nanomedicine into nephrology offers unprecedented precision and efficacy in the management of conditions ranging from AKI to CKD, including the design and preparation of multifunctional nanocarriers to overcome biological barriers and deliver therapeutics specifically to renal cells. In summary, nanomedicine holds significant potential for revolutionizing the management of AKI-to-CKD transition, thereby providing a promising opportunity for the future treatment of kidney diseases.
... The renal IRI models were established as previously reported [41]. Mice were anesthetized via intraperitoneal injection of 2.5% avertin (Sigma-Aldrich, Oakville, ON, Canada) at a dosage of 240 mg/kg. ...
Background
Acute kidney injury (AKI) is a common and severe clinical condition. However, the underlying mechanisms of AKI have not been fully elucidated, and effective treatment options remain limited. Studies have shown that immune cells play a critical role in AKI, with regulatory T cells (Tregs) being one of the most important immunosuppressive lymphocytes. Tregs proliferation can attenuate AKI, whereas depletion exacerbates kidney injury. Given that endothelial cells (ECs) are the initial cells that interact with immune cells when they invade the tissue parenchyma, ECs are closely associated with immune reactions.
Methods and Results
In this study, P-selectin binding peptide-extracellular vesicles (PBP-EVs) that target and repair ECs are engineered. Transcriptome sequencing reveals that PBP-EVs reduce the expression of inflammatory genes in AKI mice. Using high-resolution intravital two-photon microscopy (TPM), an increased recruitment of Tregs in the kidneys of AKI Foxp3-EGFP transgenic mice following PBP-EVs treatment is observed, as well as significant Lgr5⁺ renal stem cell proliferation in AKI Lgr5-CreERT2; R26mTmG mice. Additionally, PBP-EVs treatment result in reduced infiltration of inflammatory cells, pathological damage and fibrosis of AKI mice. Upon depletion of Tregs in Foxp3-DTR transgenic mice, we observe diminished therapeutic effect of PBP-EVs on AKI.
Conclusions
The experimental results indicate that PBP-EVs can promote the repair and regeneration of AKI by mitigating endothelial cell damage and subsequently modulating Tregs and the immune microenvironment. These findings provide novel insights and strategies for the treatment of AKI.
... As mentioned in section 2, these materials have already been successfully utilised to replicate the complex environments of living tissues, such as the ECM. In addition to theragnostic applications, successful hydrogel-based therapies included the treatment of kidney diseases, [29,58] wound dressing, [59] wound healing [60] and heart tissue repair. [61] Indeed, hydrogel-based technologies set the basis for the development of integrated, low-cost, and sustainable technologies that other bio-inspired materials may follow. ...
Bio‐inspired approaches in materials science and systems chemistry are yielding a variety of stimuli‐responsive and dynamic materials that are gradually changing our everyday life. However, the ability to chemically program these materials to exhibit macroscopic higher‐order behaviours such as self‐assembly, contractility, swarming, taxis, chemical communication, or predator‐prey dynamics remains an ongoing challenge. While still in its infancy, the successful fabrication of bio‐inspired materials displaying higher‐order behaviours not only will help bridging the gap between living and non‐living matter, but it will also contribute to the development of advanced materials for potential applications ranging from tissue engineering and biotechnology, to soft robotics and regenerative medicine. Our Mini‐Review will systematically discuss the higher‐order behaviours developed thus far in bio‐inspired systems, namely (i) polymer networks (ii) microbots, (iii) protocells, and (iv) prototissues. For each system it will provide key examples and highlight how the emergent behaviour could be chemically programmed.
... A novel delivery method has been initially investigated and could enhance therapeutic outcomes by mimicking the ecological environment of natural stem cells through the use of a hydrogel matrix and growth factors as a carrier. This approach could greatly improve the survival rate of stem cells [136]. The co-transplantation of CS-IGF-1C hydrogel with human placentaderived MSCs (hP-MSCs) could increase the colonization of hP-MSCs in the intestines of colitis mice and enhance the therapeutic effect of MSCs [137]. ...
Mesenchymal stem cells (MSCs) have shown great potential in the treatment of several inflammatory diseases due to their immunomodulatory ability, which is mediated by exosomes secreted by MSCs (MSC-Exs). The incidence of inflammatory bowel disease (IBD) is increasing globally, but there is currently no long-term effective treatment. As an emerging therapy, MSC-Exs have proven to be effective in alleviating IBD experimentally, and the specific mechanism continues to be explored. The gut microbiota plays an important role in the occurrence and development of IBD, and MSCs and MSC-Exs can effectively regulate gut microbiota in animal models of IBD, but the mechanism involved and whether the outcome can relieve the characteristic dysbiosis necessary to alleviate IBD still needs to be studied. This review provides current evidence on the effective modulation of the gut microbiota by MSC-Exs, offering a basis for further research on the pathogenic mechanism of IBD and MSC-Ex treatments through the improvement of gut microbiota.
... CS-IGF-1C hydrogel could shield the supplied ADSCs and further encourage the functional and structural recovery of the kidney when implanted into an ischemic kidney. In addition to giving ADSCs a synthetic niche, covalent immobilisation of IGF-1C peptide to CS hydrogel promoted the cell matrix anchoring and controlled cell proliferation and inflammation in kidney regeneration following AKI [35]. ...
Kidney Disease (KD), has a high global prevalence and accounts for one of the most prominent causes of morbidity and mortality in the twenty-first century. Despite the advances in our understanding of its pathophysiology, the only available therapy options are dialysis and kidney transplantation. Mesenchymal stem cells (MSCs) have proven to be a viable choice for KD therapy due to their antiapoptotic, immunomodulatory, antioxidative, and pro-angiogenic activities. However, the low engraftment, low survival rate, diminished paracrine ability, and delayed delivery of MSCs are the major causes of the low clinical efficacy. A number of preconditioning regimens are being tested to increase the therapeutic capabilities of MSCs. In this review, we highlight the various strategies to prime MSCs and their protective effects in kidney diseases.
Graphical Abstract
Preconditioning Strategies of Mesenchymal Stem cell in Kidney Disease
... Immobilizing IGF-1C in CS hydrogel has been shown to shield encapsulated human placental MSCs from oxidative stress by H 2 O 2 in vitro and enhance MSC engraftment in vivo. In animal models of acute kidney injury and colitis, IGF-1C-CS encapsulation has proven to enhance MSC therapeutic effects, potentially through an increased secretion of PGE2 and IL-10, the suppression of TNF-α production, and the polarization of macrophages toward the anti-inflammatory M2 phenotype [107,108] ( Table 1). ...
Mesenchymal stromal cells (MSCs) showcase remarkable immunoregulatory capabilities in vitro, positioning them as promising candidates for cellular therapeutics. However, the process of administering MSCs and the dynamic in vivo environment may impact the cell–cell and cell–matrix interactions of MSCs, consequently influencing their survival, engraftment, and their immunomodulatory efficacy. Addressing these concerns, hydrogel encapsulation emerges as a promising solution to enhance the therapeutic effectiveness of MSCs in vivo. Hydrogel, a highly flexible crosslinked hydrophilic polymer with a substantial water content, serves as a versatile platform for MSC encapsulation. Demonstrating improved engraftment and heightened immunomodulatory functions in vivo, MSCs encapsulated by hydrogel are at the forefront of advancing therapeutic outcomes. This review delves into current advancements in the field, with a focus on tuning various hydrogel parameters to elucidate mechanistic insights and elevate functional outcomes. Explored parameters encompass hydrogel composition, involving monomer type, functional modification, and co-encapsulation, along with biomechanical and physical properties like stiffness, viscoelasticity, topology, and porosity. The impact of these parameters on MSC behaviors and immunomodulatory functions is examined. Additionally, we discuss potential future research directions, aiming to kindle sustained interest in the exploration of hydrogel-encapsulated MSCs in the realm of immunomodulation.
... An indirect evidence is that medium containing serum from mice with an I/R injury decreased the viability of hMSCs and the iron concentration in such serum is increased to about 120 μM ( Figure S4C). Also, hMSCs were decreased by 70% in I/R-injured liver compared with the control group and this trend was consistent with previous reports that poor hMSC survival was found in cardiac ischaemic regions (Feng et al., 2016;Zhou et al., 2021). These results indicated that the ferroptosis induced by I/R injury could cause decrease survival of injected hMSCs in ischaemic sites. ...
Background and Purpose
The low efficacy of mesenchymal stem cells (MSCs) has restricted their application in the treatment of liver disease. Emerging evidence suggested that ferroptosis may provoke hepatocyte dysfunction and exacerbate damage to the liver microenvironment. Here, we have investigated the contribution of liver ferroptosis to the elimination and effectiveness of human MSC (hMSC). Furthermore, potential links between liver ferroptosis and aryl hydrocarbon receptors (AhR) were explored.
Experimental Approach
Two mouse models, iron supplement‐induced hepatic ferroptosis and hepatic ischaemia/reperfusion (I/R) injury, were used to identify effects of ferroptosis on hMSC pharmacokinetics (PK)/pharmacodynamics (PD).
Key Results
AhR inhibition attenuated hepatic ferroptosis and improved survival of hMSCs. hMSC viability was decreased by iron supplementation or serum from I/R mice. The AhR antagonist CH223191 reversed iron overload and oxidative stress induced by ferroptosis and increased hMSC concentration and efficacy in mouse models. Effects of CH223191 were greater than those of deferoxamine, a conventional ferroptosis inhibitor. Transcriptomic results suggested that the AhR–signal transducer and activator of transcription 3 (STAT3)–haem oxygenase 1/COX‐2 signalling pathway is critical to this process. These results were confirmed in a mouse model of hepatic I/R injury. In mice pre‐treated with CH223191, hMSC exhibited more potent protective effects, linked to decreased hepatic ferroptosis.
Conclusion and Implications
Our findings showed that ferroptosis was a critical factor in determining the fate of hMSCs. Inhibition of AhR decreased hepatic ferroptosis, thereby increasing survival and therapeutic effects of hMSCs in mouse models of liver disease.
... Feng et al. created a chitosan hydrogel with insulin-like growth factor-1 (IGF-1) binding sites as a pro-survival factor to deliver ADMSCs in a unilateral ischemia-reperfusion AKI model 15 minutes after injury. [4] Treated kidneys demonstrated improved angiogenesis and a reduction in fibrosis. ...
... For example, Gao and Feng both used luciferase labeled ADMSCs to serially track cell location in vivo after injection via their thermosensitive chitosan hydrogels under the kidney capsule in murine model of AKI. [3,4] Soranno, Lu and Rodell have used a near-infrared fluorescence (Cy5.5 or Cy7.5), covalently bound to their PEG and HA hydrogels or model biomolecules (mouse serum albumin) to longitudinally assess hydrogel degradation and therapeutic release in vivo. [15,9,10] Assessing Kidney Function after Hydrogel Therapy Until recently, the biocompatibility of hydrogels delivered subcapsularly, or intrarenally, to treat kidney disease has been limited to standard histological and biomarker evaluation. ...
Background:
Hydrogels are water-swollen networks that can be made from a variety of natural and synthetic polymers. Numerous chemistries can be utilized to formulate hydrogels that are injectable, enabling facile in situ delivery of therapeutics such as cytokines or cells.
Summary:
Cells delivered via injectable hydrogels survive injection better than cells injected in saline or media suspension. Several materials have been used to investigate the use of injectable hydrogels to treat animal models of kidney disease. Species studied to date include mice and rats. This review summarizes the various materials, encapsulated therapeutic payloads and preclinical models of kidney disease employed to investigate hydrogel injection. Transcutaneous measurements of glomerular filtration rate have demonstrated that delivery of hydrogels under the kidney capsule does not impair kidney function.
Key messages:
Studies to date have shown the safety and efficacy of hydrogel therapies to treat kidney disease, and numerous studies have demonstrated that hydrogel therapy alone reduces inflammation and fibrosis.
... Nevertheless, the challenges associated with preserving stem cells in a culture and facilitating their engraftment in the damaged tissue remain [8,9]. Additionally, another challenge in clinical practice concerns the poor long-term maintenance of stem cell functions [10,11]. ...
The deposition of stem cells at sites of injury is a clinically relevant approach to facilitate tissue repair and angiogenesis. However, insufficient cell engraftment and survival require the engineering of novel scaffolds. Here, a regular network of microscopic poly(lactic-co-glycolic acid) (PLGA) filaments was investigated as a promising biodegradable scaffold for human Adipose-Derived Stem Cell (hADSC) tissue integration. Via soft lithography, three different microstructured fabrics were realized where 5 × 5 and 5 × 3 μm PLGA ‘warp’ and ‘weft’ filaments crossed perpendicularly with pitch distances of 5, 10 and 20 μm. After hADSC seeding, cell viability, actin cytoskeleton, spatial organization and the secretome were characterized and compared to conventional substrates, including collagen layers. On the PLGA fabric, hADSC re-assembled to form spheroidal-like structures, preserving cell viability and favoring a nonlinear actin organization. Moreover, the secretion of specific factors involved in angiogenesis, the remodeling of the extracellular matrix and stem cell homing was favored on the PLGA fabric as compared to that which occurred on conventional substrates. The paracrine activity of hADSC was microstructure-dependent, with 5 μm PLGA fabric enhancing the expression of factors involved in all three processes. Although more studies are needed, the proposed PLGA fabric would represent a promising alternative to conventional collagen substrates for stem cell implantation and angiogenesis induction.
