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Mesenchymal Stem Cells Attract Endothelial Progenitor Cells via a Positive Feedback Loop between CXCR2 and CXCR4.

ABSTRACT: Mesenchymal stem cells (MSCs) can attract host endothelial progenitor cells (EPCs) to promote vascularization in tissue-engineered constructs (TECs). Nevertheless, the underlying mechanism remains vague. This study is aimed at investigating the roles of CXCR2 and CXCR4 in the EPC migration towards MSCs. In vitro, Transwell assays were performed to evaluate the migration of EPCs towards MSCs. Antagonists and shRNAs targeting CXCR2, CXCR4, and JAK/STAT3 were applied for the signaling blockade. Western blot and RT-PCR were conducted to analyze the molecular events in EPCs. In vivo, TECs were constructed and subcutaneously implanted into GFP+ transgenic mice. Signaling inhibitors were injected in an orientated manner into TECs. Recruitment of host CD34+ cells was evaluated by immunofluorescence. Eventually, we demonstrated that CXCR2 and CXCR4 were both highly expressed in migrated EPCs and indispensable for MSC-induced EPC migration. CXCR2 and CXCR4 strongly correlated with each other in the way that the expression of CXCR2 and CXCR2-mediated migration depends on the activity of CXCR4 and vice versa. Further studies documented that both of CXCR2 and CXCR4 activated STAT3 signaling, which in turn regulated the expression of CXCR2 and CXCR4, as well as cell migration. In summary, we firstly introduced a reciprocal crosstalk between CXCR2 and CXCR4 in the context of EPC migration. This feedback loop plays critical roles in the migration of EPCs towards MSCs.

SUBMITTER: Tan Y

PROVIDER: S-EPMC6915119 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mesenchymal Stem Cells Attract Endothelial Progenitor Cells via a Positive Feedback Loop between CXCR2 and CXCR4.

Tan Yingyun Y Shu Linjing L Xu Peng P Bai Shi S

Stem cells international 20191205

Mesenchymal stem cells (MSCs) can attract host endothelial progenitor cells (EPCs) to promote vascularization in tissue-engineered constructs (TECs). Nevertheless, the underlying mechanism remains vague. This study is aimed at investigating the roles of CXCR2 and CXCR4 in the EPC migration towards MSCs. <i>In vitro</i>, Transwell assays were performed to evaluate the migration of EPCs towards MSCs. Antagonists and shRNAs targeting CXCR2, CXCR4, and JAK/STAT3 were applied for the signaling blocka ...[more]

PMID: 31885605

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Project description:BackgroundEndothelial dysfunction, characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD), is a clinically significant feature of heart failure (HF). Mesenchymal stem cells (MSCs), which have pro-angiogenic properties, have the potential to restore endothelial function. Accordingly, we tested the hypothesis that MSCs increase EPC function and restore flow-mediated vasodilation (FMD).MethodsIdiopathic dilated and ischemic cardiomyopathy patients were randomly assigned to receive autologous (n = 7) or allogeneic (n = 15) MSCs. We assessed EPC-colony forming units (EPC-CFUs), FMD, and circulating levels of vascular endothelial growth factor (VEGF) in patients before and three months after MSC transendocardial injection (n = 22) and in healthy controls (n = 10).FindingsEPC-colony forming units (CFUs) were markedly reduced in HF compared to healthy controls (4 ± 3 vs. 25 ± 16 CFUs, P < 0.0001). Similarly, FMD% was impaired in HF (5.6 ± 3.2% vs. 9.0 ± 3.3%, P = 0.01). Allogeneic, but not autologous, MSCs improved endothelial function three months after treatment (Δ10 ± 5 vs. Δ1 ± 3 CFUs, P = 0.0067; Δ3.7 ± 3% vs. Δ-0.46 ± 3% FMD, P = 0.005). Patients who received allogeneic MSCs had a reduction in serum VEGF levels three months after treatment, while patients who received autologous MSCs had an increase (P = 0.0012), and these changes correlated with the change in EPC-CFUs (P < 0.0001). Lastly, human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide synthase inhibition, were rescued by allogeneic MSC conditioned medium (P = 0.006).InterpretationThese findings reveal a novel mechanism whereby allogeneic, but not autologous, MSC administration results in the proliferation of functional EPCs and improvement in vascular reactivity, which in turn restores endothelial function towards normal in patients with HF. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction.

Project description:BackgroundAdministration of endothelial progenitor cells (EPC) represents a promising option to regenerate the heart after myocardial infarction, but is limited because of low recruitment and engraftment in the myocardium. Mobilization and migration of EPC are mainly controlled by stromal cell-derived factor 1? (SDF-1?) and its receptor CXCR4. We hypothesized that adenosine, a cardioprotective molecule, may improve the recruitment of EPC to the heart.MethodsEPC were obtained from peripheral blood mononuclear cells of healthy volunteers. Expression of chemokines and their receptors was evaluated using microarrays, quantitative PCR, and flow cytometry. A Boyden chamber assay was used to assess chemotaxis. Recruitment of EPC to the infarcted heart was evaluated in rats after permanent occlusion of the left anterior descending coronary artery.ResultsMicroarray analysis revealed that adenosine modulates the expression of several members of the chemokine family in EPC. Among these, CXCR4 was up-regulated by adenosine, and this result was confirmed by quantitative PCR (3-fold increase, P<0.001). CXCR4 expression at the cell surface was also increased. This effect involved the A(2B) receptor. Pretreatment of EPC with adenosine amplified their migration towards recombinant SDF-1? or conditioned medium from cardiac fibroblasts. Both effects were abolished by CXCR4 blocking antibodies. Adenosine also increased CXCR4 under ischemic conditions, and decreased miR-150 expression. Binding of miR-150 to the 3' untranslated region of CXCR4 was verified by luciferase assay. Addition of pre-miR-150 blunted the effect of adenosine on CXCR4. Administration of adenosine to rats after induction of myocardial infarction stimulated EPC recruitment to the heart and enhanced angiogenesis.ConclusionAdenosine increases the migration of EPC. The mechanism involves A(2B) receptor activation, decreased expression of miR-150 and increased expression of CXCR4. These results suggest that adenosine may be used to enhance the capacity of EPC to revascularize the ischemic heart.

Dataset Information

Mesenchymal Stem Cells Attract Endothelial Progenitor Cells via a Positive Feedback Loop between CXCR2 and CXCR4.

Publications

Mesenchymal Stem Cells Attract Endothelial Progenitor Cells via a Positive Feedback Loop between CXCR2 and CXCR4.

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