ArticleLiterature Review

Role of the SDF-1-CXCR4 axis in stem cell-based therapies for ischemic cardiomyopathy

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Abstract

Ischemic disorders are the leading cause of mortality worldwide, current therapies only delay progression of the disease. Data suggest a role of the SDF-1-CXCR4 axis in attenuation of ischemic disorders. We discuss the importance of SDF-1-CXCR4 interactions during development and postnatal mobilization and migration of stem cells. We focus on the role of the SDF-1-CXCR4 axis in stem-cell-based applications for attenuation of ischemic cardiomyopathy. During development the SDF-1-CXCR4 axis plays a critical role in gradient-guided cell movements. In adults, the SDF-1-CXCR4 axis is involved in retention and mobilization of stem cells. Since SDF-1 is upregulated during hypoxic tissue damage, strategies to augment or stabilize SDF-1 have been utilized to target blood-derived stem cells to ischemic tissue. We exploited this concept by preventing SDF-1 degradation with dipeptidylpeptidaseIV (DPPIV) inhibition and mobilization of stem cells by G-CSF after acute myocardial infarction. This targeted CD34(+)CXCR4(+) cells to ischemic heart and attenuated ischemic cardiomyopathy. The SDF-1-CXCR4 axis plays a role in stem cell homing during embryogenesis and adulthood especially after ischemia. Preserving functional SDF-1 by DPPIV inhibition after ischemia may enhance stem cell therapies.

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... [9][10][11] CXCR4 is strongly expressed by leukocytes, including granulocytes, monocytes, T cells, B cells, and natural killer cells as well as by bone-marrow-derived progenitor cells. 12 The CXCL12/CXCR4 axis has been shown to play a pivotal role during cardiovascular development, cardiac repair, and tissue homeostasis after ischemia. 12 However, it seems that the CXCL12/CXCR4 axis has a more complex and double-edged role in cardiovascular disease. ...
... 12 The CXCL12/CXCR4 axis has been shown to play a pivotal role during cardiovascular development, cardiac repair, and tissue homeostasis after ischemia. 12 However, it seems that the CXCL12/CXCR4 axis has a more complex and double-edged role in cardiovascular disease. On one hand, previous and current data demonstrate that activation of CXCL12/CXCR4 signaling leads to attenuation of ischemic cardiomyopathy by tissue protective effects, increased neovascularization, reduced infarct size, and an improved heart function after MI. 12,13 On the other hand, the CXCL12/CXCR4 axis has also been demonstrated to have a negative impact on cardiac remodeling after myocardial infarction, potentially associated with the recruitment of proinflammatory cells to the ischemic region. ...
... 12 However, it seems that the CXCL12/CXCR4 axis has a more complex and double-edged role in cardiovascular disease. On one hand, previous and current data demonstrate that activation of CXCL12/CXCR4 signaling leads to attenuation of ischemic cardiomyopathy by tissue protective effects, increased neovascularization, reduced infarct size, and an improved heart function after MI. 12,13 On the other hand, the CXCL12/CXCR4 axis has also been demonstrated to have a negative impact on cardiac remodeling after myocardial infarction, potentially associated with the recruitment of proinflammatory cells to the ischemic region. 14 Also, two previous studies investigating a blockade of CXCR4 with the small molecule antagonist AMD3100 generated conflicting results. ...
Article
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Background The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to be a possible imaging and therapeutic target after myocardial infarction (MI). The murine-based and mouse-specific 68Ga-mCXCL12 PET tracer could be suitable for serial in vivo quantification of cardiac CXCR4 expression in a murine model of MI.Methods and ResultsAt days 1-6 after MI, mice were intravenously injected with 68Ga-mCXCL12. Autoradiography was performed and the infarct-to-remote ratio (I/R) was determined. In vivo PET imaging with 68Ga-mCXCL12 was conducted on days 1-6 after MI and the percentage of the injected dose (%ID/g) of the tracer uptake in the infarct area was calculated. 18F-FDG-PET was performed for anatomical landmarking. Ex vivo autoradiography identified CXCR4 upregulation in the infarct region with an increasing I/R after 12 hours (1.4 ± 0.3), showing a significant increase until day 2 (4.5 ± 0.6), followed by a plateau phase (day 4) and decrease after 10 days (1.3 ± 1.0). In vivo PET imaging identified similar CXCR4 upregulation in the infarct region which peaked around day 3 post MI (9.7 ± 5.0 %ID/g) and then subsequently decreased by day 6 (2.8 ± 1.0 %ID/g).Conclusion Noninvasive molecular imaging of cardiac CXCR4 expression using a novel, murine-based, and specific 68Ga-mCXCL12 tracer is feasible both ex vivo and in vivo.
... Developing strategies to promote MSCs recruitment and survival in ischemic myocardium is paramount to enhance the effectiveness of cell therapy for Am J Transl Res 2019;11 (7):4214-4231 myocardial infarction. The stromal cell-derived factor 1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) have been demonstrated to play an essential role in the recruitment of stem cells to the ischemic myocardium [10][11][12]. However, SDF-1 expression is only transiently and slightly elevated in cardiac tissues following ischemic insult [12]. ...
... Other than SDF-1, another key factor in the chemotactic SDF-1/CXCR4 signaling pathway is the receptor CXCR4 [10][11][12][13]40]. Previous studies have shown that increasing CXCR4 expression improved the engraftment of MSCs [41,42]. ...
Article
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The SDF-1/CXCR4 signaling plays a critical role in the trafficking of mesenchymal stem cells (MSCs) to the sites of tissue damage. Our recent study demonstrated that atorvastatin (ATV) treatment improved the survival of MSCs, and ATV pretreated MSCs (ATV-MSCs) exhibited enhanced engraftment to injured myocardium. In this study, we investigated whether combined treatment with ATV and ATV-MSCs enhances cardiac repair and regeneration by activating SDF-1/CXCR4 signaling in a rat model of acute myocardial infarction. Rats were randomized into eight groups: the Sham, AMI control and 6 other groups that were subjected to AMI followed by treatment with MSCs, ATV, ATV+MSCs, ATV-MSCs, ATV+ATV-MSCs, ATV+ATV-MSCs+AMD3100 (SDF-1/CXCR4 antagonist), respectively. ATV+ATV-MSCs significantly potentiated targeted recruitment of MSCs to peri-infarct myocardium and resulted in further improvements in cardiac function and reduction in scar size compared with MSCs treatment alone at 4-week after AMI. More importantly, the cardioprotective effects conferred by ATV+ATV-MSCs were almost completely abolished by AMD3100 treatment. Together, our study demonstrated that ATV+ATV-MSCs significantly enhanced the targeted recruitment and survival of transplanted MSCs, and resulted in subsequent cardiac function improvement by augmenting SDF-1/CXCR4 signaling.
... (SDF-1) and its corresponding receptor CXCR4 have been shown to play prominent roles during cardiovascular development, cardiac repair, and tissue homeostasis after ischemia [3]. We could demonstrate that a dual therapy consisting of (stem) cell mobilization with granulocyte-colony stimulating factor (G-CSF) and stabilization of SDF-1 by preventing its cleavage through inhibition of the protease CD26 increased recruitment of blood-derived progenitor cells associated with attenuated post-MI remodeling, improved myocardial function, and increased survival in mice [4]. ...
... Since SDF-1 and CXCR4 are known HIF-1α target genes [10,11], we hypothesized that DMOG-induced PH inhibition upregulates SDF-1 and CXCR4 mRNA expression in endothelial, smooth muscle, and BM cells known to express either SDF-1 or CXCR4 [3,17]. In vitro, cultivated human endothelial HMEC-1 and aortic vascular smooth muscle HAVSMC cells were treated with 500 μM of DMOG known to induce HIF-1 target gene expression [18]. ...
Article
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SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α target genes SDF-1 and CXCR4 by dimethyloxalylglycine (DMOG)-induced prolyl-hydroxylase (PH) inhibition to augment CXCR4+ cell recruitment and myocardial repair. SDF-1 and CXCR4 expression was analyzed under normoxia and ischemia ± DMOG utilizing SDF-1-EGFP and CXCR4-EGFP reporter mice. In bone marrow and heart, CXCR4-EGFP was predominantly expressed in CD45+/CD11b+ leukocytes which significantly increased after myocardial ischemia. PH inhibition with 500 μM DMOG induced upregulation of SDF-1 mRNA in human microvascular endothelial cells (HMEC-1) and aortic vascular smooth muscle cells (HAVSMC). CXCR4 was highly elevated in HMEC-1 but almost no detectable in HAVSMC. In vivo, systemic administration of the PH inhibitor DMOG without pretreatment upregulated nuclear HIF-1α and SDF-1 in the ischemic mouse heart associated with increased recruitment of CD45+/CXCR4-EGFP+/CD11b+ cell subsets. Enhanced PH inhibition significantly upregulated reparative M2 like CXCR4-EGFP+ CD11b+/CD206+ cells compared to inflammatory M2-like CXCR4-EGFP+ CD11b+/CD86+ cells associated with reduced apoptotic cell death, increased neovascularization, reduced scar size, and an improved heart function after MI. In summary, our data suggest increased PH inhibition as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to attract CXCR4+/CD11b+ cells to the ischemic heart associated with increased cardiac repair. Key messages DMOG-induced prolyl-hydroxylase inhibition upregulates SDF-1 and CXCR4 in human endothelial cells. Systemic application of DMOG upregulates nuclear HIF-1α and SDF-1 in vivo. Enhanced prolyl-hydroxylase inhibition increases mainly CXCR4+/CD11b+ cells. DMOG increased reparative M2-like CD11b+/CD206+ cells compared to M1-like cells after MI. Enhanced prolyl-hydroxylase inhibition improved cardiac repair and heart function.
... The interaction between stromal cell-derived factor 1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) has been demonstrated to play a vital role in the recruitment of stem cells to the ischemic myocardium [5][6][7][8]. It has been shown that the expression of SDF-1 in ischemic cardiac tissues is transiently elevated and peaked at 1 to 3 days after ischemic insult and decreases to the background level in the following few days [8][9][10]. ...
... Severe inflammation in myocardial microenvironment post MI is detrimental to the survival of transplanted cells. Since the interaction between SDF-1and CXCR4 plays a vital role in the engraftment of MSCs in the injured myocardium [6,9], we therefore determined the inflammation level and SDF-1 expression in infarcted hearts to further investigate potential mechanisms underlying the enhanced migration/retention observed in the day 3 MSC Fig. 4 Exo pretreatment provided a relatively low inflammatory reaction and relatively high level of SDF-1 micro-environment in infarcted hearts for transplanted MSCs to survive. a Distribution of MSCs pre-labeled with CM-Dil (red) in the infarcted hearts on 5 weeks post AMI in the groups with and without PKH67 pre-labeled Exo (green) injection. ...
Article
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Background: Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs. Methods: Exo was isolated from MSCs and delivered to an acute myocardial infarction (AMI) rat heart through intramyocardial injection with or without intravenous infusion of atrovastatin-pretreated MSCs on day 1, day 3, or day 7 after infarction. Echocardiography was performed to evaluate cardiac function. Histological analysis and ELISA test were performed to assess angiogenesis, SDF-1, and inflammatory factor expression in the infarct border zone. The anti-apoptosis effect of Exo on MSCs was evaluated using flow cytometry and Hoechst 33342 staining assay. Results: We found that intramyocardial delivery of Exo followed by MSC transplantation (in brief, Exo+MSC treatment) into MI hearts further improved cardiac function, reduced infarct size, and increased neovascularization when compared to controls treated with Exo or MSCs alone. Of note, comparing the three co-transplanting groups, intramyocardially injecting Exo 30 min after AMI combined with MSCs transplantation at day 3 after AMI achieved the highest improvement in heart function. The observed enhanced heart function is likely due to an improved microenvironment via Exo injection, which is exemplified as reduced inflammatory responses and better MSC recruitment and retention. Furthermore, we demonstrated that pre-transplantation injection of Exo enhanced survival of MSCs and reduced their apoptosis both in vitro and in vivo. Conclusions: Combinatorial delivery of exosomes and stem cells in a sequential manner effectively reduces scar size and restores heart function after AMI. This approach may represent as an alternative promising strategy for stem cell-based heart repair and therapy.
... In addition to its potent action as a vasodilator, relaxin regulates extracellular matrix and remodeling, increases angiogenesis, and improves function after ischemic injury. 68,69 Serelaxin, a recombinant human relaxin-2, has been studied in humans with acute HF, where it is tolerated, 70 and in a larger international trial has been associated with symptomatic relief. 71 Serelaxin remains under investigation primarily for the treatment of acute HF. ...
... For more information on this topic, we suggest Refs. 68,72 . ...
Article
Recovery of ventricular function occurs in a subset of patients with advanced heart failure treated with medical and/or mechanical therapy. Finding strategies that induce ventricular recovery through induction of repair, regeneration or "rejuvenation" is a long-sought goal of research programs. Cell-based strategies, use of recombinant growth and survival factors, and gene delivery are under investigation. In this brief review we highlight a few of the biological approaches in development to treat heart failure.
... Deregulation of the SDF-1α/CXCR4 axis is crucial to many pathological states and has also been found to be an important player in myocardial infarction and other hypoxic conditions, such as ischaemic cardiomyopathy 96,97 . Exploiting its cell homing properties, SDF-1α/CXCR4 axis has also been used to home cells to the ischaemic myocardium to increase myocardial salvage and improve left ventricular (LV) function [98][99][100] . ...
... It plays a crucial role in endothelial cell migration, retention, proliferation, as well as recruitment and survival of EPCs to sites of ischaemia-induced injury 229,112,230 . Therefore, SDF-1α/CXCR4 signalling in the infarcted myocardium is thought to promote recruitment and survival of adipose-derived regenerative cells, c-kit+ endogenous cardiac stem cells and bone marrow stem cells 96,98,206 . Stem cells that have been externally delivered to the ischaemic heart (e.g. ...
Conference Paper
Introduction: SDF-1α is a chemoattractant cytokine that can deliver both acute and chronic cardioprotective benefits to the heart. Although CXCR4 has been viewed as a main receptor for SDF-1α, a secondary receptor, CXCR7, has emerged as an important mediator of SDF-1α signalling. Interestingly, endothelial CXCR7 has been found to promote regeneration and ameliorate fibrosis in various tissues and organs; however, its exact role in ischaemic disease has yet to be determined. Therefore, we sought to examine the expression and function of CXCR7 in cardiovascular tissues, focusing on its potential as a novel cardioprotective strategy. Methods: RNAscope in situ hybridization, western blotting and flow cytometry were used to investigate expression and function of CXCR7 on endothelial cell lines, isolated mouse endothelial cells, and in the whole mouse heart. We examined CXCR7 downstream signalling pathways in presence and absence of CXCR7 agonists TC14012 and VUF11207 fumarate, as well as the effects of the CXCR7 agonists on endothelial cell migration and acute ischaemia-reperfusion injury. Results: CXCR7 is expressed in the adult mouse heart and in the endothelial cell lines MCEC and HUVEC. Most CXCR7 protein in the endothelial cells was observed to be intracellular under basal conditions. In line with this expression profile, exposure to CXCR7 agonists failed to activate cardioprotective protein kinases ERK1/2 and PI3K/Akt. Moreover, VUF11207 did not ameliorate acute ischaemia-reperfusion injury, whereas the role of both CXCR7 agonists in migration and angiogenesis is less clear. Conclusions: CXCR7 is expressed in the mouse vascular endothelium, but its role in activating cardioprotective signalling pathways, as well as its overall contribution to cardioprotection is unclear. Activation of the CXCR7 receptor does not appear to be a viable acute cardioprotective strategy in mice.
... Atorvastatin (ATV) treatment was also reported to have the potential to enhance natural stromal cell-derived factor-1 (SDF-1) expression in infarct region and extend its peak expression from 1 day to 1 week post-AMI [20,21]. SDF-1 is a crucial stem cell homing factor, with its G-protein coupled receptor CXC chemokine receptor 4 (CXCR4), playing a pivotal role in recruitment of transplanted MSCs [22]. Furthermore, we also found that ATV pretreatment could not only prevent MSCs from apoptosis induced by hypoxia and serum deprivation [23], but also enhance the expression of CXCR4 on the surface of MSCs, thus remarkably improving cardiac performance through targeted homing [24]. ...
... The surprising increases in both ATV -MSCs recruitment and survival in current study, which are the fundamental and bottle-neck for therapeutic efficacy in cell therapy, were mainly ascribed to the prominent effects of SDF-1-driven targeted homing and strong antiapoptotic properties of ATV -MSCs [23,24] by the combination protocol. Another contributing factor for ATV -MSCs survival was the powerful ameliorating of intense inflammatory harsh microenvironment in the infarcted region by intensive ATV treatment with strong antiinflammatory and antiapoptotic effects, as in the current study, our previous studies [17,18,23,24,51,52], and the studies of others [21,22,57,61]. To the best of our knowledge, this is the first report to find the remarkable enhancement of SDF-1 expression in infarcted myocardium by intensive ATV treatment over the entire 4-week period of AMI, and the mid-term stage (the 2nd week) of AMI was the optimal time window period of ATV -MSCs transplantation with the clinically feasible combination protocol in preclinical AMI model. ...
Article
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Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV-pretreated mesenchymal stem cells (MSCs) (ATV -MSCs) at 1 week post-acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of ATV -MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to determine the optimal time window for MSC treatment, we first assessed stromal cell-derived factor-1 (SDF-1) dynamic expression and inflammation. Next, we compared MSC recruitment and differentiation, cardiac function, infarct size, and angiogenesis among animal groups with single, dual, and triple injections of ATV -MSCs at early (Early1, Early2, Early3), mid-term (Mid1, Mid2, Mid3), and late (Late1, Late2, Late3) stages. Compared with AMI control, intensive ATV significantly augmented SDF-1 expression 1.5∼2.6-fold in peri-infarcted region with inhibited inflammation. ATV -MSCs implantation with ATV administration further enhanced MSC recruitment rate by 3.9%∼24.0%, improved left ventricular ejection fraction (LVEF) by 2.0%∼16.2%, and reduced infarct size in all groups 6 weeks post-AMI with most prominent improvement in mid groups and still effective in late groups. Mechanistically, ATV -MSCs remarkably suppressed inflammation and apoptosis while increasing angiogenesis. Furthermore, triple injections of ATV -MSCs were much more effective than single administration during early and mid-term stages of AMI with the best effects in Mid3 group. We conclude that the optimal strategy is multiple injections of ATV -MSCs combined with intensive ATV administration at mid-term stage of AMI. The translational potential of this strategy is clinically promising. Stem Cells Translational Medicine 2019.
... Migration facilitates the homing of stem cells to the site of injury for tissue repair and is an indicator of stem cell efficacy. Stress is known to promote homing of stem cells to heart by upregulation of SDF [27,28]. In adipose derived stem cells, reactive oxygen species were shown to play a key role in the proliferation and migration [29,30]. ...
... Stromal derived factor-1α (SDF-1α/CXCL12) is a CXC chemokine that is up-regulated in experimental and clinical studies of MI and regulates chemotaxis of inflammatory and progenitor cells to sites of myocardial injury, thereby beneficially impacting angiogenesis and ventricular remodelling [9][10][11][12][13]. It is a ligand for CXCR4, which is itself upregulated in studies of myocardial infraction and has been used experimentally to target progenitor cells to sites of ischaemic injury [14]. ...
Article
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Aims The chemokine stromal derived factor-1α (SDF-1α) is known to protect the heart acutely from ischaemia-reperfusion injury via its cognate receptor, CXCR4. However, the timing and cellular location of this effect, remains controversial. Methods and results Wild type male and female mice were subjected to 40 min LAD territory ischaemia in vivo and injected with either saline (control) or SDF-1α prior to 2 h reperfusion. Infarct size as a proportion of area at risk was assessed histologically using Evans blue and triphenyltetrazolium chloride. Our results confirm the cardioprotective effect of exogenous SDF-1α in mouse ischaemia-reperfusion injury and, for the first time, show protection when SDF-1α is delivered just prior to reperfusion, which has important therapeutic implications. The role of cell type was examined using the same in vivo ischaemia-reperfusion protocol in cardiomyocyte- and endothelial-specific CXCR4-null mice, and by Western blot analysis of endothelial cells treated in vitro. These experiments demonstrated that the acute infarct-sparing effect is mediated by endothelial cells, possibly via the signalling kinases Erk1/2 and PI3K/Akt. Unexpectedly, cardiomyocyte-specific deletion of CXCR4 was found to be cardioprotective per se. RNAseq analysis indicated altered expression of the mitochondrial protein co-enzyme Q10b in these mice. Conclusions Administration of SDF-1α is cardioprotective when administered prior to reperfusion and may, therefore, have clinical utility. SDF-1α-CXCR4-mediated cardioprotection from ischaemia-reperfusion injury is contingent on the cellular location of CXCR4 activation. Specifically, cardioprotection is mediated by endothelial signalling, while cardiomyocyte-specific deletion of CXCR4 has an infarct-sparing effect per se.
... As discussed above, DPP4 is able to process a number of cytokines and chemokines by cleavage of N-terminal dipeptides. Stromal cell-derived factor-1 (SDF-1), also as known as CXCL12, is a chemoattractant for T cells, hematopoietic progenitor cells, and adipose-derived regenerative cells (64)(65)(66). SDF-1 can be proteolytic cleaved by DPP4 and converted into CXCL12(3-68) (67). CXCL12 failed to induce CXCR4-mediated b-arrestin recruitment and downstream activation of IP3, Akt or ERK1/2, and thus losing its chemoattractant properties to lymphocytes. ...
Article
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Dipeptidyl-peptidase IV (DPP4), originally identified as an aminopeptidase in 1960s, is an ubiquitously expressed protease presented as either a membrane-bound or soluble form. DPP4 cleaves dipeptide off from the N-terminal of its substrates, altering the bioactivity of its substrates. Subsequent studies reveal that DPP4 is also involved in various cellular processes by directly binding to a number of ligands, including adenosine deaminase, CD45, fibronectin, plasminogen, and caveolin-1. In recent years, many novel functions of DPP4, such as promoting fibrosis and mediating virus entry, have been discovered. Due to its implication in fibrotic response and immunoregulation, increasing studies are focusing on the potential role of DPP4 in inflammatory disorders. As a moonlighting protein, DPP4 possesses multiple functions in different types of cells, including both enzymatic and non-enzymatic functions. However, most of the review articles on the role of DPP4 in autoimmune disease were focused on the association between DPP4 enzymatic inhibitors and the risk of autoimmune disease. An updated comprehensive summary of DPP4’s immunoregulatory actions including both enzymatic dependent and independent functions is needed. In this article, we will review the recent advances of DPP4 in immune regulation and autoimmune rheumatic disease.
... HIF-1α in turn up-regulates SDF-1 and its ligands, CXCR4 and CXCR7. By this mechanism SDF-1 facilitates stem cell homing to hypoxic tissues (9). Local hypoxia drives SDF-1α expression, which under steady state conditions results in the retention of stem cells in the bone marrow (10). ...
... is thought to acutely protect the myocardium from the deleterious effects of ischaemia reperfusion injury through activating cell survival signalling pathways whilst simultaneously recruiting stem cells to the injured site to reduce myocardial injury and dysfunction(182). Additionally SDF-1α has been shown to play a pivotal role in stem cell proliferation, retention, survival, cardiomyocytes repair, neoangiogenesis and ventricular remodelling following myocardial infarction(183)(184)(185)(186). This occurs through interaction with its cognate receptor CXCR4, which is a G-protein coupled receptor; this SDF-1α -CXCR4 axis is upregulated in experimental and clinical models of MI leading to reduction of ischaemia burden and preservation of ventricular function. ...
Conference Paper
Ischaemic heart disease remains the leading cause of death worldwide and its major manifestation is through an acute myocardial infarction (AMI). This usually presents as an ST segment elevation myocardial infarction (STEMI), where an acute plaque rupture leads to a thrombotic occlusion of the coronary artery rendering the myocardium ischaemic that eventually leads to cell death. The most effective strategy of treating this is via percutaneous coronary intervention (PCI) whereby the thrombus is aspirated and stent is implanted within the narrowed segment of the artery. Other treatment options include thrombolysis or emergent coronary artery bypass grafting (CABG) surgery. Although reperfusion is a prerequisite for myocardial salvage, the process itself is capable of inducing cell death in addition to that caused by myocardial ischaemia - a process termed ‘lethal reperfusion injury’. New treatment strategies are required to protect the heart against the detrimental effects of acute ischaemia-reperfusion injury (IRI). Stromal cell-derived factor 1α (SDF-1α or CXCL12), acting through its cognate receptor on target cell membranes has been recognised and demonstrated in animal models to limit myocardial infarction size ollowing acute ischaemia reperfusion injury. We have already established that SDF-1α is an important humoral factor mediating the effects of remote ischaemic conditioning (RIC) such as reducing infarction size in a rat in vivo model as well as improving functional recovery of rat cardiac papillary muscle in an ex vivo model. Whether, SDF-1α can protect human heart tissue is not known, and is investigated here using isolated human atrial trabeculae exposed to simulated IRI. A human atrial trabecular model utilising simulated ischaemiareperfusion injury was used to reiterate the existence of ischaemic preconditioning in human tissue. The model was characterised using various stabilisation, simulated ischaemia and reperfusion times and the challenges encountered with this model are discussed. Human atrial trabeculae obtained during elective cardiac surgery were suspended in organ baths and superfused with modified Tyrode’s solution. Using the optimum stabilisation, simulated ischaemia and reperfusion times, these trabeculae were then subjected to an ischaemic insult. Some of these were preceded by a preconditioning protocol whilst others were pretreated with SDF-1α prior to the simulated ischaemic insult. The end point for the human model was the functional recovery of myocardial contractility. Unlike previous experiments, the trabeculae were stretched to the peak of the Frank- Starling curve prior to assignment to various protocols. The effect of reduced number of stretches is also compared to multiple stretches. The results of this study demonstrate that (a) ischaemic preconditioning is effective in a human model despite evolution of advancing medical therapy, (b) contrary to earlier data, I was unable to demonstrate that stretch caused preconditioning of the human myocardium, (c) SDF-1α act as a preconditioning mimetic and protects it from lethal reperfusion injury and (d) the protection appears to be mediated through its cognate CXCR4 receptors and at least partly via activation of intracellular kinases such as extracellular signal-regulated kinases (ERK). In summary, despite advances in therapy, myocardial infarction is associated with considerable morbidity and mortality. The present study demonstrates the ability of SDF-1α to protect the human atrial tissue and may involve the RISK pathway akin to all forms of conditioning.
... Tissue damage related to chemotherapy, increase SDF-1a secretion during organ damage as a result of HIF-1a binding to the SDF-1a promoter and functionally increases the adhesion, migration and homing of endothelial progenitor cells to injured tissue [26].A study on rat model showed that Dimethyloxalylglycine (DMOG) is a potent drug in inducing HIF-1a and its targets genes such as SDF-1a and CXCR4 upregulation [27]. Another study showed that Hypoxia can lead to HIF-1a and SDF-1a generation as a result of affecting their gene expression so SDF-1a gene expression can be affected by HIF-1a Small interfering RNA (siRNA) too [28]. ...
Article
. Abstract Background: Cardiotoxicity is one of the most important side effects of chemotherapy and its management save myocardium from injury and its consequences. Aim: in this review we discuss cardioprotective chemokines and cardioprotective mechanisms and pathways that induce cardioprotection through cardioprotective chemokines. Method: we searched English literature articles in Google scholar and PubMed from “1990 to 2018” through ” Cardioprotection; Cardioprotective Chemokine; Chemotherapy Induced Cardiotoxicity; Cardiomyocytes; Cytokine” . Discussion: The routine cardioprotective strategies during chemotherapy such as angiotensin-converting enzyme inhibitors and β-blockers have cardioprotective effects. Cardioprotective mechanisms and strategies can offer the oncologist several methods to protect the cardiac system through using efficient cardioprotective agents. Chemokines such as SDF-1a, IL-6,IL-8,IL-12 and G-CSF are cardioprotective chemokines. Accelerating the cardioprotection through inducing cardioprotective chemokines production can be useful in chemotherapy. Conclusion: Stimulating the production of cardioprotective chemokines through the pathways which induce the production of cardioprotective chemokines can work strongly beside the β-blockers and ACE inhibitors. The ambiguous point in cardioprotective pathways is that JAK2/STAT3 pathway which is linked to IL-6 production pathway, which induce intracellular adhesion molecule-1 in the area of the ischemia in myocardium and this process is not benefit in cardioprotection however IL-6 induce cardiomyocytes regeneration so it enhance our dull vision about IL-6. Finally there are several choices which can increase cardioprotection during the chemotherapy and if we overcome the boundaries in
... Whereas the injection of cells through an interventional catheter typically represents a one-time event, 4-6 the long-term use of drugs that enhance the cardiac homing of circulating or neighboring mesenchymal stem cells could provide an ongoing supply of cells with reparative potential that could conceivably sustain cardiac regeneration for long periods of time. [7][8][9] If the capacity for regeneration is impaired in heart failure, 10 this deficiency could be addressed if physicians were able to channel mesenchymal stem cells to the heart efficiently to foster cardiac rejuvenation. Stromal cell-derived factor-1 (SDF-1) and its cognate receptor CXCR4 play a crucial role in the homing of cells with reparative potential to injured tissue. ...
Article
The injection of mesenchymal stem cells into the injured myocardium to induce cardiac regeneration has yielded disappointing results, conceivably because cells with cardioreparative potential must be supplied for long periods of time to produce a salutary effect. Accordingly, investigators have devised ways of directing such cells to the heart on an ongoing basis: by enhancing the action of endogenous peptides that function as cardiac homing signals (eg, stromal cell-derived factor-1). Stromal cell-derived factor-1 is released during acute cardiac injury and heart failure, but it has a short half-life because of degradation by dipeptidyl peptidase-4. Inhibition of dipeptidyl peptidase-4 potentiates the actions of stromal cell-derived factor-1 and, theoretically, could enhance cardiac recovery. However, in large-scale trials in patients with type 2 diabetes mellitus, dipeptidyl peptidase-4 inhibitors have not reduced the risk of atherosclerotic ischemic events, and they have unexpectedly increased the risk of heart failure, most probably heart failure with a preserved ejection fraction. Such an outcome might be explained if the channeling of mesenchymal stem cells to the heart by the actions of stromal cell-derived factor-1 (especially from nearby adipose tissue) were followed by the transformation of these cells into fibroblasts rather than cardiomyocytes. This concern has been supported by experimental studies; the resulting fibrosis would be expected to exacerbate the pathophysiological derangements that lead to heart failure with a preserved ejection fraction. Given the widespread use of dipeptidyl peptidase-4 inhibitors, the possibility that these drugs potentiate the cardiac homing of mesenchymal stem cells that cause myocardial fibrosis (rather than repair) warrants further study.
... The results suggest that SDF-1a may be one of the humoral factors by which RIPC protects in the target organ. SDF-1a, through binding to its receptor for CXCR4, has been previously shown to act on the ischemic area after myocardial infarction, promote cell repair, and reduce ischemia-reperfusion injury [30], and even improve left ventricular systolic function [31]. Studies have shown that SDF-1a-CXCR4 can promote the activation of PI3K, MEK1/2, and JAK via G1a protein activation, which in turn activates AKT, ErK1/2 and STATS, finally activating the SAFE and RISK signal transduction pathways, both of which are particularly important in mitigating ischemia-reperfusion injury [32] and may affect the mitochondrial ATP-sensitive potassium channel (mKATP) and mitochondrial permeability transition pore (MPTP), thereby reducing ischemia-reperfusion injury. ...
Article
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Background The aim of this study was to evaluate the role of remote ischemic postconditioning (RIPC) of the upper arm on protection from cardiac ischemia-reperfusion injury following primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). Material/Methods Eighty patients with STEMI were randomized into two groups: primary PCI (N=44) and primary PCI+RIPC (N=36). RIPC consisted of four cycles of 5 minutes of occlusion and five minutes of reperfusion by cuff inflation and deflation of the upper arm, commencing within one minute of the first PCI balloon dilatation. Peripheral venous blood samples were collected before PCI and at 0.5, 8, 24, 48, and 72 hours after PCI. Levels of creatine kinase-MB (CK-MB), serum creatinine (Cr), nitric oxide (NO), and stromal cell-derived factor-1α (SDF-1α) were measured. The rates of acute kidney injury (AKI) and the estimated glomerular filtration rate (eGFR) were calculated. Results Patients in the primary PCI+RIPC group, compared with the primary PCI group, had significantly lower peak CK-MB concentrations (P<0.01), a significantly increased left ventricular ejection fraction (LVEF) (P=0.01), a significantly lower rate of AKI (P<0.01) a significantly increased eGFR (P<0.01), and decreased area under the curve (AUC) of CK-MB, NO and SDF-1α. Conclusions RIPC of the upper arm following primary PCI in patients with acute STEMI might provide cardiac and renal protection from ischemia-reperfusion injury via the actions of SDF-1α, and NO.
... Chemokine SDF-1 plays an important role in the chemotaxis, homing, proliferation and survival of bone marrow stem cells expressing chemokine receptor-4 (CXCR4). Disruption of the SDF-1/CXCR4 axis in bone marrow induced by G-CSF leads to the migration of stem cells towards an SDF-1 gradient [12]. Enhanced cardiac expression of SDF-1 was found after myocardial infarction [13]. ...
Article
We tested the hypothesis that daunorubicin (DAU) cardiotoxicity alters expression of cytokines involved in stem cell migration and homing. Male Wistar rats were treated with daunorubicin to induce acute DAU cardiomyopathy (6x3 mg/kg, i.p., every 48 hr, DAU-A) or subchronic DAU cardiomyopathy (15 mg/kg, i.v., DAU-C). The left ventricle was catheterized. The animals were killed 48 hr (DAU-A) and 8 weeks (DAU-C) after the last dose of DAU. Expression of foetal genes (Nppa, Nppb), isomyosins (Myh6, Myh7), sources of oxidative stress (Abcb8, gp91phox), cytokines (Sdf-1, Cxcr4, Scf, Vegf, Hgf, Igf-1), markers of cardiac progenitor (c-kit, Atnx-1), endothelial progenitor (CD34, CD133) and mesenchymal (CD44, CD105) stem cells were determined by qRT-PCR in left ventricular tissue. Reduced body weight, decreased left ventricular weight and function, elevated Nppa, Nppb, Myh7 were observed in both models. Myh6 decreased only in DAU-C, which had a 35% mortality. Up-regulated gp91phox and down-regulated Abcb8 in DAU were present only in DAU-C where we observed markedly decreased expressions of Scf and Vegf as well as expressions of stem cell markers. Down-regulation of cytokines and stem cell markers may reflect impaired chemotaxis, migration and homing of stem cells and tissue repair in the heart in subchronic but not acute model of DAU cardiomyopathy. This article is protected by copyright. All rights reserved.
... For example, CXCR4 is a chemokine receptors that specifically binds to stromal derived factor-1 (SDF-1). SDF-1 has been extensively found in inflammatory regions, such as the area of ischemic, where it recruits CXCR4 expressing cells [202,203]. Hematopoietic stem cells largely express the CXCR4 when they are in bone marrow. However, it is reported that the expression level of CXCR4 is largely decreased during ex vivo expansion, thereby losing their migration property towards SDF-1 sites [204]. ...
... To check the effects of CCs and their parental cells, neonatal rat cardiac myocytes were incubated with them. Addition of CCs increased the expression of stromal-derived factor, a cardioprotective agent, and also acted as a ligand to CXCR4 + stem cells [270]. The study also showed an increase in capillary density in the area incubated with the CCs (Fig. 1b). ...
Article
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Mesenchymal stem cells have been used for cardiovascular regenerative therapy for decades. These cells have been established as one of the potential therapeutic agents, following several tests in animal models and clinical trials. In the process, various sources of mesenchymal stem cells have been identified which help in cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Although mesenchymal cell therapy has achieved considerable admiration, some challenges still remain that need to be overcome in order to establish it as a successful technique. This in-depth review is an attempt to summarize the major sources of mesenchymal stem cells involved in myocardial regeneration, the significant mechanisms involved in the process with a focus on studies (human and animal) conducted in the last 6 years and the challenges that remain to be addressed. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0341-0) contains supplementary material, which is available to authorized users.
... [1][2][3][4][5] For example, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (MI), wherein it is thought to mitigate adverse ventricular remodelling. Its mechanism of action is reportedly as a chemo-attractant for a variety of cell types expressing its cognate G protein-coupled receptor, CXCR4, including mesenchymal stem cells (MSCs), adiposederived regenerative cells, c-kit + endogenous cardiac stem cells and T lymphocytes, [6][7][8][9] which subsequently have beneficial paracrine effects. [10] It has also been implicated in acute cardioprotection via its binding to myocardial CXCR4 and subsequent activation of the reperfusion injury salvage kinase pathway. ...
Article
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Background Stromal derived factor-1α (SDF-1α/CXCL12) is a chemokine that is up-regulated in diseases characterised by tissue hypoxia, including myocardial infarction, ischaemic cardiomyopathy and remote ischaemic conditioning (RIC), a technique of cyclical, non-injurious ischaemia applied remote from the heart that protects the heat from lethal ischaemia-reperfusion injury. Accordingly, there is considerable interest in SDF-1α as a potential biomarker of such conditions. However, SDF-1α is rapidly degraded and inactivated by dipeptidyl peptidase 4 and other peptidases, and the kinetics of intact SDF-1α remain unknown. Methods & results To facilitate investigation of full-length SDF-1α we established an ELISA using a novel recombinant human antibody we developed called HCI.SDF1. HCI.SDF1 is specific to the N-terminal sequence of all isoforms of SDF-1 and has a comparable KD to commercially available antibodies. Together with a detection antibody specific to the α-isoform, HCI.SDF1 was used to specifically quantify full-length SDF-1α in blood for the first time. Using RIC applied to the hind limb of Sprague-Dawley rats or the arms of healthy human volunteers, we demonstrate an increase in SDF-1α using a commercially available antibody, as previously reported, but an unexpected decrease in full-length SDF-1α after RIC in both species. Conclusions We report for the first time the development of a novel recombinant antibody specific to full-length SDF-1. Applied to RIC, we demonstrate a significant decrease in SDF-1α that is at odds with the literature and suggests a need to investigate the kinetics of full-length SDF-1α in conditions characterised by tissue hypoxia.
... Furthermore, BMP-2 treatment alone or in combination with collagen matrix on the dental pulp cutting surface can promote the formation of prosthetic dentin (Razzouk and Sarkis 2012;Seo et al. 2015). SDF-1α is a chemokine that belongs to the CXC subfamily, which has been reported to play a critical role in the recruitment, migration and differentiation of hematopoietic stem cells, mesenchymal stem cells (MSC) and endothelial progenitor cells (Zaruba and Franz 2010;Park et al. 2018;De-Colle et al. 2017). Recently, it was reported that SDF-1α promotes odontoblast differentiation of dental pulp cells and the combination of SDF-1α and dental pulp stem cells (DPSC) could promote pulp regeneration in vivo (Nam et al. 2017;Kim et al. 2014). ...
Article
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Pulp-dentin regeneration in the apical region of immature permanent teeth represents a significant clinical challenge. Tissue engineering approaches using bioactive molecules and scaffolds may have the potential to regenerate the natural apical structure of these teeth, representing a superior alternative to existing treatment regimens. The aims of this study are (i) to evaluate the VitroGel 3D system, an animal origin-free polysaccharide hydrogel, as a possible injectable scaffold for pulp-dentin regeneration and (ii) to investigate the effects of stromal cell-derived factor-1α (SDF-1α) and bone morphogenetic protein-2(BMP-2) cotreatment on odontogenic differentiation of human stem cells from apical papilla (SCAP) cultured in the VitroGel 3D system. The morphology, viability and proliferation of SCAP cultured in the VitroGel 3D system were measured via scanning electron microscopy (SEM), live and dead cell staining and CCK-8 assays. Alkaline phosphatase (ALP) activity, real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and Western blot analysis were further used to evaluate the odontogenic differentiation of SCAP cultured in the VitroGel 3D system in vitro. Finally, the odontogenic differentiation was assessed in vivo through ectopic subcutaneous injection. The results showed that SCAP cultured in 3D hydrogel demonstrated favorable viability and proliferation. SDF-1α and BMP-2 cotreatment enhanced odontogenic differentiation-related gene and protein expression in vitro and promoted odontogenic differentiation of SCAP in vivo. In conclusion, the present study demonstrated that the VitroGel 3D system promoted SCAP proliferation and differentiation. Moreover, SDF-1α cotreatment had synergistic effects on BMP-2-induced odontogenic differentiation of human SCAP cultured in the VitroGel 3D system both in vitro and in vivo.
... Tissue damage related to chemotherapy, increase SDF-1a secretion during organ damage as a result of HIF-1a binding to the SDF-1a promoter and functionally increases the adhesion, migration and homing of endothelial progenitor cells to injured tissue [26].A study on rat model showed that Dimethyloxalylglycine (DMOG) is a potent drug in inducing HIF-1a and its targets genes such as SDF-1a and CXCR4 upregulation [27]. Another study showed that Hypoxia can lead to HIF-1a and SDF-1a generation as a result of affecting their gene expression so SDF-1a gene expression can be affected by HIF-1a Small interfering RNA (siRNA) too [28]. ...
Article
Background: Cardiotoxicity is one of the most important side effects of chemotherapy and its management save myocardium from injury and its consequences. Aim: in this review we discuss cardioprotective chemokines and cardioprotective mechanisms and pathways that induce cardioprotection through cardioprotective chemokines. Method: we searched English literature articles in Google scholar and PubMed from “1990 to 2018” through ” Cardioprotection; Cardioprotective Chemokine; Chemotherapy Induced Cardiotoxicity; Cardiomyocytes; Cytokine” . Discussion: The routine cardioprotective strategies during chemotherapy such as angiotensin-converting enzyme inhibitors and β-blockers have cardioprotective effects. Cardioprotective mechanisms and strategies can offer the oncologist several methods to protect the cardiac system through using efficient cardioprotective agents. Chemokines such as SDF-1a, IL-6,IL-8,IL-12 and G-CSF are cardioprotective chemokines. Accelerating the cardioprotection through inducing cardioprotective chemokines production can be useful in chemotherapy. Conclusion: Stimulating the production of cardioprotective chemokines through the pathways which induce the production of cardioprotective chemokines can work strongly beside the β-blockers and ACE inhibitors. The ambiguous point in cardioprotective pathways is that JAK2/STAT3 pathway which is linked to IL-6 production pathway, which induce intracellular adhesion molecule-1 in the area of the ischemia in myocardium and this process is not benefit in cardioprotection however IL-6 induce cardiomyocytes regeneration so it enhance our dull vision about IL-6. Finally there are several choices which can increase cardioprotection during the chemotherapy and if we overcome the boundaries inconfirming the efficiency of cardioprotective chemokines and the activation of them through using several mechanisms we will break through the difficulties over chemotherapy-induced cardiotoxicity.
... SDF-1a/ CXCR4 was found as the main axis involved in migration and homing of the stem cells in myocardial infarction, and using G-CSF and inhibitor of DPP4 was efficient in inducing the stem cells migration with an additional positive impact on heart function. [24] We found that expressions of Sdf-1a and Cxcr4 at mRNA levels in the heart were downregulated after DAU, but the administration of PFIL or LINA did not affect this decrease. CXCR4 is expressed by endothelial progenitor and mesenchymal stem cells, [10,15] so we further determined markers of both categories of stem cells. ...
Article
Objective: Daunorubicin (DAU) downregulates cytokines promoting stem cell migration and homing into the heart, reducing cardiac regeneration after anticancer chemotherapy. Pegfilgrastim (PFIL) protects from DAU-induced neutropenia but its cardioprotective potential remains unclear. We tested whether pegfilgrastim and a dipeptidyl peptidase-4 inhibitor linagliptin, potential enhancers of stem cells migration and homing, would improve DAU-cardiomyopathy. Methods: DAU (7.5 mg/kg, i.v.) was administered to male Wistar rats to induce cardiotoxicity. Pegfilgrastim (100 µg/kg, s.c.) was administered 24h after DAU, and linagliptin was administered orally for 8 weeks (5 mg/kg/day, LINA). Cardiac damage markers (Nppa, Myh6, Myh7, Gp91phox), cytokines (Sdf-1alpha, Mcp-1, Vegf, Hgf, Igf-1), stem cell markers (Cxcr4, Ccr2, Cd34, Cd133, Cd44, Cd105) were determined by qRT-PCR. Key findings: Decreased Myh6, elevated Myh7 Nppa, and Gp91phox were not ameliorated by PFIL + LINA. Downregulated expressions of cytokines (Vegf, Sdf-1alpha) and stem cells markers (Cxcr4, Cd34, Cd133, and Cd105) remained decreased after PFIL + LINA. DAU-induced upregulation of Mcp-1, Ccr2 and Cd44 was further potentiated by PFIL + LINA. PFIL + LINA normalised expression of Hgf and Igf-1. Conclusion: Although PFIL + LINA failed in universal potentiation of stem cells migration and homing, the expression of stem cell markers Ccr2 and Cd44 in the heart potentially increased through the preservation of Hgf, Igf-1 and upregulation of Mcp-1.
... The success of stem-cell therapy depends on the migration and survival of the transplanted cells [40,41]. Therefore, enhancing the migration ability and survival of BMSCs are the key to optimize stem cell therapy in wounds. ...
Article
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Background: The transplantation of bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutic strategy for wound healing. However, the poor migration capacity and low survival rate of transplanted BMSCs in wounds weaken their potential application. Objective: To identify the optimal protocol for BMSCs preconditioned with H2O2 and improve the therapeutic efficacy using H2O2-preconditioned BMSCs in wound healing. Methods: Mouse BMSCs were exposed to various concentrations of H2O2, and the key cellular functional properties were assessed to determine the optimal precondition with H2O2. The H2O2-preconditioned BMSCs were transplanted into mice with full-thickness excisional wounds to evaluate their healing capacity and tissue engraftment. Results: Treatment BMSCs with 50 μM H2O2 for 12 h could significantly enhance their proliferation, migration, and survival by maximizing the upregulation of cyclin D1, SDF-1, and its receptors CXCR4/7 expressions, and activating the PI3K/Akt/mTOR pathway, but inhibiting the expression of p16 and GSK-3β. Meanwhile, oxidative stress-induced BMSC apoptosis was also significantly attenuated by the same protocol pretreatment with a decreased ratio of Bax/Bcl-2 and cleaved caspase-9/3 expression. Moreover, after the identification of the optimal protocol of H2O2 precondition in vitro, the migration and tissue engraftment of transfused BMSCs with H2O2 preconditioning were dramatically increased into the wound site as compared to the un-preconditioned BMSCs. The increased microvessel density and the speedy closure of the wounds were observed after the transfusion of H2O2-preconditioned BMSCs. Conclusions: The findings suggested that 50 μM H2O2 pretreated for 12 h is the optimal precondition for the transplantation of BMSCs, which gives a considerable insight that this protocol may be served as a promising candidate for improving the therapeutic potential of BMSCs for wound healing.
... SDF-1 and VCAM-1 are expressed through endothelial cells, osteoblasts, and the bone marrow stromal cells, which are the biological components of the HSC niche in the bone marrow. It is then expected that many mobilizing chemicals activate CD34+ HSC mobilization following the targeting of these two key interactions [47]. ...
Article
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Chemokines are chemoattractants that can regulate cell movement and adhesion. SDF-1 [stromal cell-derived factor-1 (SDF-1)] is a homeostatic CXC chemokine. SDF-1 and its receptors [CXC chemokine receptor 4 (CXCR4)] form a signaling pathway that plays critical roles in different pathological and physiological mechanisms, including embryogenesis, wound healing, angiogenesis, tumor growth, and proliferation. Therefore, the current review aimed to summarize the related studies that addressed the molecular signature of the SDF-1/CXCR4 pathway and to explain how this axis is involved in normal events.
... Many studies have shown that EPCs can migrate to the damaged site in endothelium and mediate its regeneration, promote the neovascularization in ischemic lesions, and thus alleviate the progression of AS (Hill et al., 2003;Naito et al., 2012;Xu et al., 2014). Stromal-cell-derived factor-1α (SDF-1α), a well-known chemokine expressed in multiple tissues and cells such as ECs, has been demonstrated to be related to cardiac protection (Zaruba and Franz, 2010). Upregulated SDF-1α in ischemic tissues has been shown to be capable of mediating the mobilization of BM-derived EPCs into peripheral blood and their homing to the damaged site and then promoting the neovascularization of ischemic tissues (Yin et al., 2010;Rath et al., 2016). ...
Article
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Atherosclerosis (AS) seriously impairs the health of human beings and is manifested initially as endothelial cells (ECs) impairment and dysfunction in vascular intima, which can be alleviated through mobilization of endothelial progenitor cells (EPCs) induced by stromal-cell-derived factor-1α (SDF-1α). A strong inverse correlation between HDL and AS has been proposed. The aim of the present work is to investigate whether 4F, an apolipoprotein A-I (apoA-I, major component protein of HDL) mimic peptide, can upregulate SDF-1α in mice and human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. The protein levels of SDF-1α were measured by ELISA assay. Protein levels of HIF-1α, phosphorylated Akt (p-Akt), and phosphorylated ERK (p-ERK) were evaluated by Western blotting analysis. The results show that L-4F significantly upregulates protein levels of HIF-1α, Akt, and ERK, which can be inhibited by the PI3K inhibitor, LY294002, or ERK inhibitor, PD98059, respectively. Particularly, LY294002 can downregulate the levels of p-ERK, while PD98059 cannot suppress that of p-Akt. D-4F can upregulate the levels of HIF, p-Akt, and p-ERK in the abdominal aorta and inferior vena cava from mice. These results suggest that 4F promotes SDF-1α expression in ECs through PI3K/Akt/ERK/HIF-1α signaling pathway.
... IL-1β mediates the recruitment and activation of in ammatory leukocytes, at the same time delays the activation of myo broblasts. In vitro studies have shown that inhibiting IL-1β can reduce cardiomyocyte apoptosis [45]. IL-6 is also upregulated in infarcted myocardium through IL-6 receptor β Subunit and activate JAK/STAT cascade to regulate in ammation [46]. ...
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Background: To study the protective effect of BMSC overexpressing SDF-1α on myocardial ischemia/reperfusion (I/R), to improve the limitation that only part of BMSC is recruited to the site of myocardial injury in the treatment of ischemic heart disease. It provides a new scheme for stem cell therapy for clinical treatment of reperfusion injury. Methods: Collect blood samples from PCI patients and healthy individuals to detect PMN and SDF-1α expression; Construction of BMSC overexpressing SDF-1α (oe-SDF-1α); In the case of no intervention or intervention by BMSC respectively, cell level: the migration ability of PMN to hypoxia/reoxygenation (H/R) cardiomyocytes and the expression of SDF-1α, CXCR4, apoptosis, oxidative stress and other indicators of cardiomyocytes were detected; In vivo level: PMN, SDF-1α, CXCR4, oxidative stress and inflammatory factor levels were detected in I/R mice. And carry out statistical analysis. Results: ① In the clinic, compared with the control group, the expression levels of SDF-1α and PMN in the blood of PCI patients increased. ② Under H/R conditions, cardiomyocytes express and secrete SDF-1α, activate PMN migration and infiltration mediated by SDF-1/CXCR4 signal pathway, promote cardiomyocyte apoptosis and increase the level of oxidative stress; oe-SDF-1α has a stronger ability to migrate to H/R cardiomyocytes and has more repair ability than BMSC.It is more suitable as a tool cell for stem cell therapy. ③ The expression levels of SDF-1α and PMN are increased in I/R mice. oe-SDF-1α can reduce the ability of PMN to reside to the damaged part of myocardial tissue significantly, thereby reducing myocardial tissue damage, oxidative stress, inflammatory factor levels in I/R mice. Conclusions: The SDF-1/CXCR4 biological axis not only plays an important role in BMSC migration, but also helps to enhance the therapeutic effect of BMSC-based therapy. Oe-SDF-1α has a more repairing effect on reducing cell damage caused by PMN, and can be used as a new type of cell for the treatment of IRI.
... The chemokine CXCL12 plays an important role in cell migration, differentiation, tissue homeostasis of leukocytes and hematopoietic stem and progenitor cells, and is critically involved in ischemic tissue repair [3,16,20,22]. However, cell-and tissue-specific effects of CXCL12 are barely understood, limiting the implementation of targeted therapies. ...
Article
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The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12−/−). SM-CXCL12−/− mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12−/− mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12−/− mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.
... In addition to double-labelling immunohistochemistry to detect MAP1B + CD146 + and STRO-1 + CD146 + cells, a quantitative gene-expression assay was performed to assess CD146 and MAP1B mRNA expressions in the pulp. Moreover, to investigate the mechanisms behind stem cell recruitment, mRNA and protein levels of stem cell factor (SCF) and stromal-derived factor 1 (SDF-1) were assessed, which are major homing factors that have recently emerged as being important in the field of regenerative medicine (Urbich et al. 2005, Kuang et al. 2008, Zaruba & Franz 2010. ...
Article
Aim: To examine the effect of inflammatory stimuli on the proliferation/migration of dental pulp stem cells by assessing the responses of stem cell-associated marker-expressing cells in rat incisors to lipopolysaccharide (LPS) stimulation in vivo. Methodology: The crowns of rat incisors were removed, and the coronal pulp chamber was instrumented. After haemostasis, an absorbent point soaked in LPS was inserted into the cavity, which was then sealed. At 3 h, 12 h, and 48 h after LPS application, pulp tissues were subjected to double-immunoperoxidase labelling using two of the antibodies against microtubule-associated protein 1B (MAP1B), CD146, and STRO-1. For gene expression analysis, total RNA was extracted, and mRNA expression levels of stem cell factor (SCF), stromal-derived factor 1 (SDF-1), CD146, and MAP1B were analysed with real-time polymerase-chain reaction. SCF and SDF-1 protein levels were also assessed by western blot. Statistical analysis was performed by Kruskal-Wallis non-parametric analysis of variance, followed by Mann-Whitney U-tests with Bonferroni correction. Results: The density of MAP1B(+) CD146(+) cells and STRO-1(+) CD146(+) cells in LPS-stimulated pulp tissue increased significantly at 3 h and exhibited a 4- to 6-fold increase at 48 h as compared with the density observed in normal pulp tissue (P < 0.05). The expression of CD146 mRNA in LPS-stimulated pulp showed significant upregulation at 3 h as compared with that observed in normal pulp tissue (P < 0.05). MAP1B, SCF, and SDF-1 mRNA levels also showed significant upregulation at 3 h and 72 h (P < 0.05), and western blot analysis revealed increases in SCF and SDF-1 following LPS stimulation. Conclusions: LPS-stimulated pulp tissue exhibited upregulation of stem cell-differentiation/migration markers and showed increases in the number of MAP1B(+) CD146(+) and STRO-1(+) CD146 stem-like cells. This article is protected by copyright. All rights reserved.
... Importantly, EVs also promoted an increase in stromal cell-derived factor 1 (SDF-1) concentration in the heart, which, along with the overexpression of its receptor CXC chemokine receptor 4 (CXCR4) in BM-MSCs by pre-treatment with atorvastatin, increased cell homing to the myocardium [65]. The interaction between SDF-1 and CXCR4 has been investigated and exploited in other studies as a relevant axis mediating cell recruitment in ischemic cardiomyopathies [94,95]. The administration of EVs secreted from BM-MSCs pre-treated with atorvastatin also induced better heart recovery than control BM-MSC-EVs in other studies [66]. ...
Article
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Extracellular vesicles (EVs) are constituted by a group of heterogeneous membrane vesicles secreted by most cell types that play a crucial role in cell–cell communication. In recent years, EVs have been postulated as a relevant novel therapeutic option for cardiovascular diseases, including myocardial infarction (MI), partially outperforming cell therapy. EVs may present several desirable features, such as no tumorigenicity, low immunogenic potential, high stability, and fine cardiac reparative efficacy. Furthermore, the natural origin of EVs makes them exceptional vehicles for drug delivery. EVs may overcome many of the limitations associated with current drug delivery systems (DDS), as they can travel long distances in body fluids, cross biological barriers, and deliver their cargo to recipient cells, among others. Here, we provide an overview of the most recent discoveries regarding the therapeutic potential of EVs for addressing cardiac damage after MI. In addition, we review the use of bioengineered EVs for targeted cardiac delivery and present some recent advances for exploiting EVs as DDS. Finally, we also discuss some of the most crucial aspects that should be addressed before a widespread translation to the clinical arena.
... Based on our findings it is hypothesized that the administration of the putative MayDay protein, or an analogue thereof may have therapeutic applications in the recruitment of MSCs to damaged or diseased tissue. SDF-1 is possibly the best studied chemotactic agent in this class, having been evaluated for the treatment of renal ischemia [69] and ischemic cardiomyopathy [70], traumatic brain injury [71] and the repair of cognitive ability and cortical dendritic spine rescue [72]. In human studies, a gene therapy trial overexpressed SDF-1 in patients with ischemic heart disease, demonstrated improvements to patient outcomes [73]. ...
Article
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Soft tissue is composed of cells surrounded by an extracellular matrix that is made up of a diverse array of intricately organized proteins. These distinct components work in concert to maintain homeostasis and respond to tissue damage. During tissue repair, extracellular matrix proteins and their degradation products are known to influence physiological processes such as angiogenesis and inflammation. In this study we developed a discovery platform using a decellularized extracellular matrix biomaterial to identify new chemotrophic factors derived from the extracellular matrix. An in vitro culture of RAW.264 macrophage cells with the biomaterial ovine forestomach matrix led to the identification of a novel~12 kDa chemotactic factor, termed 'MayDay', derived from the N-terminal 31-188 sequence of decorin. The recombinant MayDay protein was shown to be a chemotactic agent for mesen-chymal stromal cells in vitro and in vivo. We hypothesize that the macrophage-induced cleavage of decorin, via MMP-12, leads to the release of the chemotactic molecule MayDay, that in turn recruits cells to the site of damaged tissue.
... Based on our findings it is hypothesized that the administration of the putative MayDay protein, or an analogue thereof may have therapeutic applications in the recruitment of MSCs to damaged or diseased tissue. SDF-1 is possibly the best studied chemotactic agent in this class, having been evaluated for the treatment of renal ischemia [69] and ischemic cardiomyopathy [70], traumatic brain injury [71] and the repair of cognitive ability and cortical dendritic spine rescue [72]. In human studies, a gene therapy trial overexpressed SDF-1 in patients with ischemic heart disease, demonstrated improvements to patient outcomes [73]. ...
Article
Full-text available
Soft tissue is composed of cells surrounded by an extracellular matrix that is made up of a diverse array of intricately organized proteins. These distinct components work in concert to maintain homeostasis and respond to tissue damage. During tissue repair, extracellular matrix proteins and their degradation products are known to influence physiological processes such as angiogenesis and inflammation. In this study we developed a discovery platform using a decellularized extracellular matrix biomaterial to identify new chemotrophic factors derived from the extracellular matrix. An in vitro culture of RAW.264 macrophage cells with the biomaterial ovine forestomach matrix led to the identification of a novel ~12 kDa chemotactic factor, termed ‘MayDay’, derived from the N-terminal 31–188 sequence of decorin. The recombinant MayDay protein was shown to be a chemotactic agent for mesenchymal stromal cells in vitro and in vivo. We hypothesize that the macrophage-induced cleavage of decorin, via MMP-12, leads to the release of the chemotactic molecule MayDay, that in turn recruits cells to the site of damaged tissue.
... The success of stem-cell therapy depends on the migration and survival of the transplanted cells [35,36]. Therefore, enhancing the migration ability and survival of BMSCs are the key to optimize stem cell therapy in wounds. ...
Preprint
Full-text available
Background The transplantation of bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutic strategy for wound healing. However, the poor migration capacity and low survival rate of transplanted BMSCs in wounds weaken their potential application. Objective The optimal protocol for BMSCs preconditioned with H2O2 was investigated, and the therapeutic efficacy of preconditioned BMSCs in wounds was evaluated. Methods Mouse BMSCs were exposed to various concentrations of H2O2, and their functions were assessed; The H2O2-preconditioned BMSCs were transplanted into mice with full-thickness excisional wounds. Wound analysis was performed to assess the transplantation efficacy. Results Treatment BMSCs with 50 µM H2O2 for 12 h could enhance their proliferation, migration and survival by maximizing up-regulation the cyclin D1, SDF-1 and its receptors CXCR4/7 expressions, and activating the PI3K/Akt/mTOR pathway, but inhibiting the expression of p16 and GSK-3β. Meanwhile, oxidative stress-induced-BMSCs apoptosis was significantly attenuated by an obviously decreased ratio of Bax/Bcl-2 and cleaved caspase-9/3 expression. After transplantation of BMSCs, the migration of H2O2 preconditioned-BMSCs into the wounds was dramatically increased compared to un-preconditioned-BMSCs, and had an increased microvessel density and wound closure speed. Conclusions The findings suggested that 50 µM H2O2 pretreated for 12 h is the optimal precondition for the transplantation of BMSC, which gives a considerable insight that this protocol may be served as a promising candidate for improving the therapeutic potential of BMSCs for wound healing.
... The American Heart Association recently confirmed the importance of a more comprehensive understanding of the underlying key regulators, diagnostic markers, and therapeutic targets, which determine the development and resulting complications of CAD. SDF-1 is a long known chemokine which is expressed in many tissue types including endothelial cells and the myocardium, and has been implicated in cardiac protection [16]. In the setting of acute myocardial ischemia, cardioprotection by SDF-1α was repeatedly shown to provide protective effects through the interaction with its receptor CXCR4 [6,[17][18][19][20][21]. ...
Article
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In the present observational study, we measured serum levels of the chemokine stromal cell-derived factor-1α (SDF-1α) in 100 patients undergoing cardiac surgery with cardiopulmonary bypass at seven distinct time points including preoperative values, myocardial ischemia, reperfusion, and the postoperative course. Myocardial ischemia triggered a marked increase of SDF-1α serum levels whereas cardiac reperfusion had no significant influence. Perioperative SDF-1α serum levels were influenced by patients' characteristics (e.g., age, gender, aspirin intake). In an explorative analysis, we observed an inverse association between SDF-1α serum levels and the incidence of organ dysfunction. In conclusion, time of myocardial ischemia was identified as the key stimulus for a significant upregulation of SDF-1α, indicating its role as a marker of myocardial injury. The inverse association between SDF-1α levels and organ dysfunction association encourages further studies to evaluate its organoprotective properties in cardiac surgery patients.
... Numerous studies have confirmed that SDF-1 is an important component of the microenvironments into which stem cells are transplanted. SDF-1 is also a potent chemotactic signal (Liekens et al., 2010;Marcello, 2010;Zaruba and Franz, 2010;Tang et al., 2011). Local SDF-1 expression near the site of myocardial infarction is closely related to the effects of stem cell transplantation. ...
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Background: Stem cell therapy of acute myocardial infarction (AMI) is proving to be a promising approach to repair the injured myocardia. The time window for stem cell transplantation is crucial yet difficult to determine since it produces different therapeutic effects at different times after myocardial infarction. Stromal cell-derived factor-1 (SDF- 1) plays a pivotal role in the mobilization, homing, proliferation, and differentiation of transplanted stem cells. Here, by using ultrasound molecular imaging via targeted microbubbles, we determined the dynamic expression of SDF-1 in a swine model of AMI in vivo. Methods: Twenty-four miniswine were randomly selected for the control group and the AMI model group, which underwent ligation of the left anterior descending coronary artery (LAD). The AMI animals were randomly divided into six experimental groups according to the duration of the myocardial infarction. All animals were subjected to ultrasound molecular imaging through injections with targeted microbubbles (T + T group) or nontargeted control microbubbles (T + C group). The values of the myocardial perfusion parameters (A, β, and A × β) were determined using Q-Lab (Philips ultrasound, version 9.0), and the expression level of SDF-1 was analyzed by real-time polymerase chain reaction (RT-PCR). Results: Our results showed that the expression of SDF-1 gradually increased and peaked at 1 week after AMI. The trend is well reflected by ultrasound molecular imaging in the myocardial perfusion parameters. The A, β, and A × β values correlated with SDF-1 in the T + T group (r = 0.887, 0.892, and 0.942; P < 0.05). Regression equations were established for the relationships of the A, β, and A × β values (X) with SDF-1 (Y): Y = 0.699X − 0.6048, Y = 0.4698X + 0.3282, and Y = 0.0945X + 0.6685, respectively (R 2 = 0.772, 0.7957, and 0.8871; P < 0.05). Conclusions: Our finding demonstrated that ultrasound molecular imaging could be used to evaluate the expression dynamics of SDF-1 after AMI.
... However, the number of endogenous therapeutic cells is usually not sufficient to recover a large injury site. Stem or progenitor cells have been applied to rescue ischemic injury in clinical trials, such as myocardial infarction or stroke [6,7]. Bone marrow mesenchymal stem cells (MSCs) have the characteristics of self-renewal and multipotency [8][9][10]. ...
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Background Bone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are used to repair hypoxic or ischemic tissue. However, the underlining mechanism of resistance in the hypoxic microenvironment and the efficacy of migration to the injured tissue are still unknown. The current study aims to understand the hypoxia resistance and migration ability of MSCs during differentiation toward endothelial lineages by biochemical and mechanical stimuli. MethodMSCs were harvested from the bone marrow of 6–8-week-old Sprague–Dawley rats. The endothelial growth medium (EGM) was added to MSCs for 3 days to initiate endothelial differentiation. Laminar shear stress was used as the fluid mechanical stimulation. ResultsApplication of EGM facilitated the early endothelial lineage cells (eELCs) to express EPC markers. When treating the hypoxic mimetic desferrioxamine, both MSCs and eELCs showed resistance to hypoxia as compared with the occurrence of apoptosis in rat fibroblasts. The eELCs under hypoxia increased the wound closure and C-X-C chemokine receptor type 4 (CXCR4) gene expression. Although the shear stress promoted eELC maturation and aligned cells parallel to the flow direction, their migration ability was not superior to that of eELCs either under normoxia or hypoxia. The eELCs showed higher protein expressions of CXCR4, phosphorylated Akt (pAkt), and endogenous NFκB and IκBα than MSCs under both normoxia and hypoxia conditions. The potential migratory signals were discovered by inhibiting either Akt or NFκB using specific inhibitors and revealed decreases of wound closure and transmigration ability in eELCs. Conclusion The Akt and NFκB pathways are important to regulate the early endothelial differentiation and its migratory ability under a hypoxic microenvironment.
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New cell-based therapeutic strategies are being developed in response to the shortcomings of available treatments for heart disease. Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Cell therapy approaches include attempts to reinitiate cardiomyocyte proliferation in the adult, conversion of fibroblasts to contractile myocytes, conversion of bone marrow (BM) stem cells into cardiomyocytes, and transplantation of myocytes or other cells into injured myocardium. Basics and techniques of cell therapy have been described in a special report on this topic (Jain 2011). Applications in cardiovascular disorders will be described in this chapter including methods of delivery of cells.
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An emerging trend in tissue engineering and regenerative medicine is the design of scaffolds that recapitulate a stem cell’s extracellular microenvironment, or “niche” (Cushing and Anseth 2007; Tibbitt and Anseth 2009). While the exact constituents of a stem cell niche are not well characterized, it is generally believed that morphogens, immobilized extracellular matrix (ECM) components, cell–cell interactions, and matrix elasticity are the major determinants that direct stem cell self-renewal or differentiation (Lutolf and Hubbell 2005). Research over the years has accumulated fundamental knowledge about stem cell biology in vitro. Most of the results were obtained from experiments conducting on flat, rigid, and two-dimensional (2D) tissue culture polystyrene (TCPS). These 2D environments, however, might not truly reproduce what a stem cell experiences in vivo, where relevant biological and biophysical cues are produced in a far more complex and spatially and temporally regulated manner. In fact, results from numerous studies have demonstrated that, compared with cell culture on TCPS, stem cells behave differently when cultured in three-dimensional (3D) matrices (Liu and Roy 2005; Ingber et al. 2006; Lee et al. 2008b; Lund et al. 2009). Artificial matrices of synthetic or natural origins have been developed for culturing stem cells in 3D (Lee et al. 2008b; Lund et al. 2009). While natural ECM components, such as collagen and laminin, provide intrinsic biological recognition sites for cell attachment and migration, these natural matrices are ill-defined and poorly controlled with respect to their compositions and mechanical properties, respectively. Furthermore, one cannot afford to overlook the immunogenicity problems associated with allogenic or xenogenic materials, since this significantly limits the clinical translatability/relevance of stem-cell-based therapy. Matrices fabricated from synthetic polymers, on the other hand, provide well-defined and user-controllable chemical and physical properties (Nuttelman et al. 2008). The use of synthetic matrices, however, is not without challenges, insofar as synthetic polymers usually lack biological motifs for cellular recognition. Hence, significant efforts have been dedicated to fabricating synthetic polymeric scaffolds functionalized with biomimetic motifs that permit cellular interaction.
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Bone is a complex tissue-organ system integrating multiple components in hierarchical layers of molecular cues, cellular communities, and networking highways. Bone moves through space and time in a dynamic manner modulated by homeostatic mechanisms nuanced through a coordinated intercalation of biological and biomechanical rhythms. The price we vertebrate species pay for maintaining this magnificently orchestrated tissue-organ is daunting. Bone is the most metabolically expensive tissue in the human body. For every ounce of bone, a pound of soft tissue is required for maintenance [1]. Moreover, the human skeletal system must be rugged in order to handle years of cyclic loading at high forces on the order of kilonewtons, and highly sensitive to the calibrated kinetics of calcium and phosphate release in order to maintain meticulously modulated ion levels [2]. Consequently, the intrinsic design of bone and the dynamics that sustain it are an instructional core for regenerative bone therapeutics. In this chapter we will introduce the profoundly compelling biodynamic structural marvel that gives shape to the amorphous mass in which it is wrapped and provides the fulcrums and pulleys that propel our anatomy along the avenues and boulevards of our towns. We will probe the blueprint of bone as a defining mold that guides and mentors attempts in the laboratory to design and develop compositions to repair and regenerate this structural tour de force.
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Background: One of the best and most effective applied and tolerable approaches for cardioprotecion is the regular exercise. In situation of exercise activity and even cardiac ischemic injury, the activity of the myocardial stem cells and their recruiting factors are changed so that contribute the adaptation and repairment of the myocardium. The aim of this study was to investigate the effect of myocardial preconditioning with high intensive interval training on SDF-1a myocardial levels, CXCR4 receptors and c-kit after acute myocardial infarction in male rats. Methods: 20 male Wistar rats (8 week old ,weight 234.8 ± 5.7 g) were randomly divided into 4 groups of control (C), training (T), myocardial infraction (MI) and training+ myocardial infraction (T+MI). The training groups performed two weeks of high intensity interval training in four sections. Each section included two or three days of practice sessions and two sessions each per a day. The number or intensity of the intervals increased in each section. SDF-1, CXCR4 and C-Kit proteins were measured by the Western blot method in the myocardial tissue and myocardial injury enzymes (CK, LDH, troponin T) were measured in serum. Results: The results of this study showed that that SDF-1, CXCR4 and C-Kit had a significant increase after two weeks of high intensity interval training and myocardial infraction. Also, serum enzyme measurements showed a positive effect of exercise, so that in the myocardium injury enzymes significantly increased in the myocardial infarction group compared with the other three groups, training and training- myocardial infarction (P<0.001). As well as, there was a significant difference between the groups of training -myocardial infarction in all of the enzymes of the myocardium injury compared to the control and training groups. Conclusions: Even short terms of high intensity interval training can increase the levels of proteins SDF1-a, CXCR4 and C-Kit in order to cardioprotection against myocardial injury through recruitment stem cells.
Chapter
The most abundant proteins in the extracellular matrix are members of the collagen family. Collagen is composed largely of the amino acids glycine, proline, and hydroxyproline, which are often present as Gly?X?Y repeats (where X and Y are either proline or hydroxyproline). Tropocollagen is the subunit of collagen fibrils formed of three polypeptide strands (each offset by one amino acid), approximately 300 nm long and 1.5 nm in diameter. Each of the three parallel polypeptide strands is in a left-handed helical polyproline II-type coil with three residues to form a right-handed triple helix. The tropocollagen units assemble in a parallel, quarter-staggered arrangement. There is a 40-nm gap, also called the ?hole zone,? between the ends of each of these units, with 27 nm of overlap between adjacent units. The chemistry underlying the formation of these tissues is all quite similar; the fundamental differences depend on their hierarchical fibrillar architectures. More than 20 human collagens have been reported, many of which display a 67-nm periodicity, due to the axial packing of the individual collagen molecules [1, 2]. Collagens constitute an important family of proteins in the vertebrate body and serve as extracellular matrix molecules for many soft and hard connective tissues, including cornea, skin, tendon, cartilage, and bone [1, 3]. Collogen provides cellular recognition for regulating cell attachment and functions. Collagen favors cell adhesion that is normally found in joint tissues and those exogenous cells embedded in a collagen delivery device. Almost all of the connective tissues with collagen fibrils as the basic building blocks have remarkably similar chemistry at the macromolecular and fibrillar levels of structure. However, differentiation in the hierarchical structure takes place as these fibrils are arranged in the specific architecture required for the construction of special tissues each with unique functions, which is generally considered the function of other, non-collagen, molecules.
Chapter
Stem cells are defined by their unique ability to self-renew and produce progeny that differentiate into specialized cells. Naturally occurring stem cells are usually broken down into three principal categories. Embryonic stem cells (ESCs) are derived from the inner cell mass of a preimplantation embryo and are considered pluripotent, meaning able to produce cell types of all three germ layers. Second, adult somatic stem cells exist at a very low frequency in almost all tissues and organs of the body and are usually considered lineage-restricted to the subset of cell types that make up their tissue of origin. Lastly, fetal stem cells can be obtained from various fetal tissues, including primordial germ cells, blood, liver, bone marrow and amniotic fluid, as well as extra-embryonic tissues such as the placenta and umbilical cord. In terms of multipotentiality these fetal stem cells lie somewhere between ESCs and more committed adult somatic stem cells. A new fourth, artificially generated type of stem cell now exists, namely the so-called induced pluripotent stem (iPS) cell, which results from the transcriptional reprogramming of a terminally differentiated somatic cell. Each one of these stem cell types has advantages and disadvantages in cell-based therapies and undoubtedly no one cell type will fit all applications. For example, ES cells are attractive because of their inherent plasticity, but their derivation elicits ethical concerns and the likelihood of forming teratomas after transplantation makes them, for now, a therapeutic dead end. Adult somatic stem cells, like bone marrow mesenchymal stromal cells (BM-MSCs) are being used clinically [45, 62], but their applications are restricted by limited proliferative capacity in culture and a predisposition to differentiate down primarily mesenchymal lineages. iPS cells have been shown to be genetically unstable and also have the potential to form teratomas after transplantation [33], especially if the efficiency of the differentiation protocols is not optimized. Fetal stem cells can be isolated from two distinct sources, the fetus proper and the extra-embryonic support tissues such as the amniotic fluid, placenta, and umbilical cord (especially Wharton’s jelly) [1]. Isolating stem cells from the fetus is replete with moral, ethical, and legal concerns and will therefore not be discussed further here. The use of fetal stem cells from extra-embryonic tissues, on the other hand, elicits no ethical or moral concerns because their isolation does not put a developing fetus at risk.
Chapter
Hydrogels are an excellent scaffold structure for numerous applications in tissue engineering and regenerative medicine. In particular, they can be used as cell and drug carriers to deliver such therapeutic components directly and locally [1]. Hydrogels can be injected and crosslinked in situ, reducing the need for risky invasive surgeries [2]. In addition, hydrogels can mimic the natural extracellular matrix (ECM) environment, and allow one to control cellular and tissue functions as well as the transport of nutrients and bioactive molecules [3, 4]. Fumarate-based hydrogels are synthetic polymers, allowing flexible control of physical, mechanical, and degradative properties for a desired application [4]. Fumaric acid, the fundamental component of these hydrogel scaffolds, is an unsaturated organic acid that is commonly found in the human body and can be metabolized through the Krebs cycle [5–7]. Polymer chains that contain fumarate units crosslink easily via the unsaturated double bonds and degrade through hydrolysis of the ester bonds in the fumarate group [6–9]. Furthermore, the biodegradable nature of these hydrogels allows neotissue ingrowth and eliminates the need for further surgery to remove the implanted scaffold [5, 10].
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Hypoxic-ischemic encephalopathy (HIE) is a complex condition which is associated with high mortality and morbidity. However, few promising treatments for HIE exist. In the present study, the central objective was to identify the therapeutic effect of pilose antler polypeptides (PAP) on HIE in rats. Sprague-Dawley (SD) rats (14 days old) were used and divided into three groups, including control group, hypoxic-ischemia (HI) group and PAP group. After 21 days of treatment, locomotor activity was improved in PAP-treated rats, brain atrophy was decreased and cerebral edema was mitigated to some extent. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis indicated that PAP administration decreased the expressions of inflammatory cytokines and apoptosis genes in hippocampus compared with HI group. Furthermore, the mRNA expressions of genes related to neurotrophic factors were significantly increased in the hippocampus. In addition, the expressions of oxidative stress markers were all down-regulated after PAP administration. Moreover, PAP up-regulated both the mRNA and protein levels of SDF1 and CXCR4, which may activate the SDF1/CXCR4 axis to moderate brain injury. These results suggest that PAP may be potentially used in the treatment of HIE.
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Stem cell therapy is a promising strategy for recovering of injured cardiac tissue after acute myocardial infarction. The effects promoted by preventive physical training, beneficial for regeneration, are not yet understood on stem cell homing. In the present study, we evaluated the effect of preventive physical training on cell homing activation and associated mechanisms after acute myocardial infarction and therapy with adipose-derived stem cells in spontaneously hypertensive rats (SHR). Forty female SHR were allocated in sedentary (S), sedentary SHAM (S-SHAM), sedentary AMI (S-AMI), sedentary with cell therapy (S-ICT), aerobically trained (T), trained SHAM (T-SHAM), trained AMI (T-AMI) and trained with cell therapy (S-ICT) groups. Cell therapy was performed through the infusion of 2 × 105 ADSC/0.05 mL at the moment of AMI. Molecular markers of cell homing (SDF-1/CXCR4), inflammatory response (myeloperoxidase and cardiac expression of iNOS, gp91phox and NFkB), vasoconstrictor agents (Ang II and ET-1) and an angiogenesis inducer (VEGF) were measured. Functional capacity and echocardiographic parameters were also evaluated. Preventive physical training associated with cell therapy was able to reduce left ventricle ejection fraction losses in infarcted animals. Results demonstrated activation of the SDF-1/CXCR4 axis by physical training, besides a reduction in vasoconstrictor and systemic inflammatory responses. Physical training prior to AMI was able to induce a cardioprotective effect and optimize the reparative mechanism of cell therapy in an animal model of hypertension.
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Myocardial infarction is one of the leading causes of mortality and morbidity worldwide. While transplantation of several cell types into the infarcted heart has produced promising preclinical results, clinical studies using analogous human cells have shown limited structural and functional benefits. In Dog and Human, we have described a type of muscle-derived stem cells termed MuStem cells that efficiently promoted repair of injured skeletal muscle. Enhanced survival rate, long-term engraftment, and participation in muscle fiber formation were reported, leading to persistent tissue remodeling and clinical benefits. Considering these features that are restricted or absent in cells tested so far for myocardial infarction, we wanted to investigate the capacity of human MuStem cells to repair infarcted heart. Their local administration in immunodeficient rats 1 week after induced infarction resulted in reduced fibrosis and increased angiogenesis 3 weeks post-transplantation. Importantly, foci of human fibers were detected in the infarct site. Treated rats also showed attenuated left ventricle dilation and preservation of contractile function. Interestingly, no spontaneous arrhythmias were observed. Our findings support the potential of MuStem cells, which have already been proposed as therapeutic candidates for dystrophic patients, to treat myocardial infarction and position them as attractive tool for muscle regenerative medicine.
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Diabetic foot ulcer (DFU) has become a major medical, social and economic concern worldwide. It is highly desirable to develop promising new solutions to effectively and appropriately treat DFU. In recent years, investigators have used an innovative technology called proximal tibial cortex transverse distraction (PTCTD) to treat DFU and have achieved satisfactory results in terms of improved wound healing and circumvention of amputation as a consequence of enhanced neovascularization and perfusion of the ulcerated feet after the operation, but the underlying mechanism has not been explored. Previous studies have suggested that in addition to stimulating osteogenesis, bone distraction also facilitates neovascularization, which may be associated with the chemokine stromal cell-derived factor-1 (SDF-1). As an important member of the chemokine family, SDF-1 is primarily responsible for the homing and migration of endothelial progenitor cells (EPCs) or bone marrow-derived mesenchymal stem cells (BMSCs), and plays a central role in the process of neovascularization. In vivo or in vitro experiments show that bone distraction can induce the expression of SDF-1 and increase its plasma concentration. Moreover, some researchers have found that an insufficient level of SDF-1 in the circulation and wounds of patients with DFU can lead to impaired neovascularization. Therefore, we believe that SDF-1 plays an important role in promoting neovascularization of DFU as a result of bone distraction. We summarize the currently relevant literature to put forward an undisclosed but meaningful mechanism of bone distraction in the treatment of DFU.
Article
Recent studies have emphasized the role of vascular adventitia inflammation and immune response in hypertension. It has been reported that stromal cell-derived factor-1 (SDF-1) plays various biological functions through its receptors C-X-C motif chemokine receptor 4 (CXCR4) and CXCR7 in tumor growth and tissue repair. However, it is unclear that whether SDF-1/CXCR4/CXCR7 axis is involved in hypertensive vascular remodeling. In the present study, the involvement of SDF-1/CXCR4/CXCR7 axis was evaluated with lentivirus-mediated shRNA of SDF-1 and CXCR7, CXCR4 antagonist AMD3100 and CXCR7 agonist VUF11207 in angiotensin II (AngII)-induced hypertensive mice and in cultured adventitial fibroblasts (AFs). Results showed that AngII infusion markedly increased SDF-1 expressed in vascular adventitia, but not in media and endothelium. Importantly, blockade of SDF-1/CXCR4 axis strikingly potentiated AngII-induced adventitial thickening and fibrosis, as indicated by enhanced collagen I deposition. In contrast, CXCR7 shRNA largely attenuated AngII-induced adventitial thickness and fibrosis, whereas CXCR7 activation with VUF11207 significantly potentiated AngII-induced adventitial thickening and fibrosis. In consistent with these in vivo study, CXCR4 inhibition with AMD3100 and CXCR7 activation with VUF11207 aggravated AngII-induced inflammation, proliferation and migration in cultured AFs. In summary, these results suggested that SDF-1 exerted opposing effects through CXCR4 and CXCR7 in AngII-induced vascular adventitial remodeling.
Chapter
The utilization of transplanted stem cells in regenerative medicine has been studied extensively as a potential therapy to repair or replace tissues that are lost due to trauma, congenital deformities, tumor resections, or infectious diseases [1–3]. The current cell transplantation model in regenerative medicine is founded on the principle that the application of transplanted stem cells could repopulate and regenerate damaged or diseased tissues, with restored tissue functions and homeostasis. However, cell transplantation is faced with a multitude of clinical and cell culture complications including the complexity of the multistep surgical procedures, donor-site trauma, immune rejection for allogeneic and xenogeneic cells, cell phenotypic variations due to in-vitro culture techniques, potential tumorigenesis associated with long-term cell expansion, failure of exogenous cell engraftment, and uncertainties and difficulties in the regulatory approval process [4–8]. The difficulties in the clinical application of stem cell transplantation are in strong contrast to the results of multiple experimental studies that demonstrate different levels of efficacy of cell delivery in a number of disease models such as Parkinson's disease [9, 10], blood cancers and diseases [11, 12], and muscle and spinal disorders/injuries [13, 14]. For a number of regenerative medicine applications, the use of stem cell transplantation might not be competitive with the cost-effectiveness of current clinical treatment modalities in the dental and musculoskeletal fields, including titanium joint replacements, dental implants, and operative dental procedures [15–17]. Alternatively, the concept of endogenous stem/progenitor cell recruitment in regenerative medicine is based on the idea that native stem/progenitor cells that already reside within mature tissue can be stimulated and functionally enhanced to repopulate, repair, and/or regenerate damaged tissues [18]. Relative to stem cell transplantation, the application of endogenous stem cell recruitment in regenerative medicine is still in its infancy. The combination of the use of biological factors, release technology, biomaterials, and bioengineered scaffolds to enhance endogenous stem cell recruitment seems very promising for potential use in translational regenerative medicine. However, further scientific experimentation is warranted, since many scientific questions concerning the mechanistic details remain unresolved and it will be necessary to validate the efficacy of this approach for clinical application.
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This study aimed at analysing the endogenous stem cell circulation in patients suffering from idiopathic dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). Cytokines in peripheral blood were analysed using enzyme-linked immunosorbent assay and circulating CD34(+) stem cell populations (CD34(+)CD133(+), CD34(+)CD31(+), CD34(+)CXCR-4(+)) were measured by flow cytometry in DCM patients (n = 25), ICM patients (n = 15), and controls (n = 10). Explanted DCM (n = 5), ICM (n = 4) and normal hearts (n = 5) were analysed for the expression of several homing factors [stromal cell-derived factor-1 (SDF-1), Stem cell factor (SCF), HIF-1a, vascular cell adhesion molecule (VCAM), and Hepatocyte growth factor] by quantitative real-time polymerase chain reaction (PCR). SDF-1 was significantly elevated and positively correlated with brain natriuretic peptide (BNP) in peripheral blood of DCM and ICM patients showing the same New York heart association- (NYHA) class. In DCM patients circulating CD34(+) cell populations were significantly increased in comparison to ICM patients and controls. mRNA of SDF-1, SCF, HIF-1a, and VCAM related to glyceraldehyde-3-phosphate dehydrogenase was significantly upregulated in ICM hearts when compared with DCM hearts and controls. Myocardial homing factors are upregulated in ICM when compared with DCM hearts. Reduced homing of stem cells might therefore explain the increased number of CD34(+) cells in DCM patients. These findings may open a new insight into the pathology and the treatment of idiopathic DCM.
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Muscle regeneration occurs through activation of quiescent satellite cells whose progeny proliferate, differentiate, and fuse to make new myofibers. We used a transgenic Pax7-ZsGreen reporter mouse to prospectively isolate stem cells of skeletal muscle by flow cytometry. We show that Pax7-expressing cells (satellite cells) in the limb, head, and diaphragm muscles are homogeneous in size and granularity and uniformly labeled by certain cell surface markers, including CD34 and CD29. The frequency of the satellite cells varies between muscle types and with age. Clonal analysis demonstrated that all colonies arising from single cells within the Pax7-sorted fraction have myogenic potential. In response to injury, Pax7(+) cells reduce CD34, CD29, and CXCR4 expression, increase in size, and acquire Sca-1. When directly isolated and cultured in vitro, Pax7(+) cells display the hallmarks of activation and proliferate, initially as suspension aggregates and later distributed between suspension and adherence. During in vitro expansion, Pax7 (ZsGreen) and CD34 expression decline, whereas expression of PSA-NCAM is acquired. The nonmyogenic, Pax7(neg) cells expand as Sca1(+) PDGRalpha(+) PSA-NCAM(neg) cells. Satellite cells expanded exclusively in suspension can engraft and produce dystrophin(+) fibers in mdx(-/-) mice. These results establish a novel animal model for the study of muscle stem cell physiology and a culture system for expansion of engraftable muscle progenitors.
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Ischemic cardiomyopathy is one of the main causes of death, which may be prevented by stem cell-based therapies. SDF-1alpha is the major chemokine attracting stem cells to the heart. Since SDF-1alpha is cleaved and inactivated by CD26/dipeptidylpeptidase IV (DPP-IV), we established a therapeutic concept--applicable to ischemic disorders in general--by combining genetic and pharmacologic inhibition of DPP-IV with G-CSF-mediated stem cell mobilization after myocardial infarction in mice. This approach leads to (1) decreased myocardial DPP-IV activity, (2) increased myocardial homing of circulating CXCR-4+ stem cells, (3) reduced cardiac remodeling, and (4) improved heart function and survival. Indeed, CD26 depletion promoted posttranslational stabilization of active SDF-1alpha in heart lysates and preserved the cardiac SDF-1-CXCR4 homing axis. Therefore, we propose pharmacological DPP-IV inhibition and G-CSF-based stem cell mobilization as a therapeutic concept for future stem cell trials after myocardial infarction.
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CXCL12, a ligand for the chemokine receptor CXCR4, is well known in mediating neural progenitor cell (NPC) migration during neural development. However, the effects of CXCL12 on human NPC proliferation and its associated signaling pathways remain unclear. The transcription factor, FOXO3a, a downstream target of Akt-1, is critical for cell cycle control and may also play an important role in regulating NPC proliferation. In this study, we found that CXCL12 promotes human NPC proliferation as determined by the proliferation marker Ki67 and BrdU incorporation. This CXCL12-mediated NPC proliferation was associated with an increase in Akt-1 and FOXO3a phosphorylation in a time- and dose-dependent manner. The CXCR4 antagonist (T140) or inhibitors for G proteins (Pertussis toxin) and phosphoinositide 3-kinase (PI3K) (LY294002) abolished CXCL12-mediated NPC proliferation and phosphorylation of Akt-1 and FOXO3a. The roles of Akt-1 and FOXO3a in CXCL12-mediated NPC proliferation were further investigated by using adenoviral over-expression in NPCs. Over-expression of dominant-negative Akt-1 or wild-type FOXO3a in NPC abrogated CXCL12-mediated proliferation. These data suggest that CXCL12-mediated NPC proliferation is reliant upon the phosphorylation of Akt-1 and FOXO3a and gives insight to an essential role of CXCL12 in neurogenesis. Understanding this mechanism may facilitate the development of novel therapeutic targets for NPC proliferation during neurogenesis.
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Side population cells are a rare subset of cells found in the adult heart that are highly enriched for stem and progenitor cell activity. Recent studies have suggested that Sca1+/CD31- cardiac side population cells are capable of differentiation into cardiomyocytes in vitro. However, the response of these cells to myocardial injury remains unknown in vivo. Sca1+/CD31- cardiac side population cells were isolated from mouse (C57BL6/J) hearts by FACS. These cells were labeled and delivered via an intramyocardial injection into an infracted mouse heart. The differentiation potential of these cells was determined by immunohistochemistry two weeks later. We further tested the migration potential and the relationship of SDF-1alpha/CXCR4 to these cells. The transplanted cells were found to express cardiomyocyte or endothelial cell specific markers. Furthermore, when these cells were transplanted into non-infarct myocardium after myocardial infarction, they were found in the damaged myocardium. Consistent with their homing property, we found that SDF-1alpha and CXCR4 were up-regulated in the damaged myocardium and on Sca1+/CD31- cardiac side population cells respectively following myocardial infarction. We also show that SDF-1alpha induced migration of Sca1+/CD31- cardiac side population cells in vitro. Our results have suggested that Sca1+/CD31- cardiac side population cells are able to migrate into damaged myocardium from non-ischemic area of the heart and differentiate into both cardiomyocyte- and endothelial-like cells following acute ischemic injury. The SDF-1alpha/CXCR4 system might play an important role in the migration of these cells.