SDF‐1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction

Abstract

Stem cell transplantation at the time of acute myocardial infarction (AMI) improves cardiac function. Whether the improved cardiac function results from regeneration of cardiac myocytes, modulation of remodeling, or preservation of injured tissue through paracrine mechanisms is actively debated. Because no specific stem cell population has been shown to be optimal, we investigated whether the benefit of stem cell transplantation could be attributed to a trophic effect on injured myocardium. Mesenchymal stem cells secrete SDF-1 and the interaction of SDF-1 with its receptor, CXCR4, increases survival of progenitor cells. Therefore, we compared the effects of MSC and MSC engineered to overexpress SDF-1 on cardiac function after AMI. Tail vein infusion of syngeneic MSC and MSC:SDF-1 1 day after AMI in the Lewis rat led to improved cardiac function by echocardiography by 70.7% and 238.8%, respectively, compared with saline controls 5 wk later. The beneficial effects of MSC and MSC:SDF-1 transplantation were mediated primarily through preservation, not regeneration of cardiac myocytes within the infarct zone. The direct effect of SDF-1 on cardiac myocytes was due to the observation that, between 24 and 48 h after AMI, SDF-1-expressing MSC increased cardiac myocyte survival, vascular density (18.2+/-4.0 vs. 7.6+/-2.3 vessels/mm2, P<0.01; SDF-1:MSC vs. MSC), and cardiac myosin-positive area (MSC: 49.5%; mSC:SDF-1: 162.1%) within the infarct zone. There was no evidence of cardiac regeneration by the infused MSC or endogenous cardiac stem cells based on lack of evidence for cardiac myocytes being derived from replicating cells. These results indicate that stem cell transplantation may have significant beneficial effects on injured organ function independent of tissue regeneration and identify SDF-1:CXCR4 binding as a novel target for myocardial preservation.

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

“…This conclusion is supported by our data that inhibition of CXCR4 by miRNA-CXCR4 significantly reduced homing of transplanted MSCs to the ischemic myocardium resulting in limited myocardial regeneration and angiogenesis. Our data support recent reports that the SDF-1α/CXCR4 interaction is important for MSCs migration to the infarcted myocardium and angiogenesis [6,38]. However, the approach in this study used the delivery of CXCR4 over-expressing MSCs rather than delivery of SDF-1α expressing MSCs.…”

“…Besides their migratory role, these CXCR4 positive MSCs participated in neovascularization and differentiated into new myocytes. In addition, MSCs secrete or express SDF-1α [34,35] and its interaction with CXCR4 increases survival of progenitor cells [6]. SDF-1α could serve as an adhesive molecule by binding CXCR4-expressing cells to the vessel wall [36], which is consistent with our study that a high degree of CXCR4 expression is observed in the vascular endothelial cells.…”

“…However, it was also reported that SDF-1α expression alone did not increase vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) which may explain the ineffectiveness of MSCs in the repair of damaged heart [37]. Another recent study showed lack of myocytes regeneration by overexpressing SDF-1α in the infarcted area despite improvement of cardiac function [6]. This protection could occur by recruiting the anti-apoptotic kinases ERK and Akt [36].…”

“…SDF-1α, secreted by cells within ischemic myocardium, is a potent chemo-attractant for cells expressing CXCR4. In a recent report, Zhang et al have shown that transplantation of SDF-1α over-expressing MSCs could enhance the cardioprotective effects of MSCs [6]. Although mobilization of endothelial progenitor cells (EPCs) in the setting of acute myocardial infarction has been observed [3], little is known about the effect of MSCs over-expressing CXCR4 on their mobilization and engraftment within infarcted myocardium.…”

The immune system and cardiac repair

“…Transplantation of cells engineered to express SDF-1 into the peri-infarct zone following coronary occlusion in the rat resulted in attenuated adverse remodeling [116]. The beneficial effects of SDF-1 may be due to therapeutic stem cell homing into the injured myocardium resulting in neovascularization and enhanced preservation of cardiomyocytes [118]. Local delivery of SDF-1 in the infarct may exert beneficial actions by augmenting vasculogenesis and by protecting ischemic cardiomyocytes from apoptosis without inducing cardiomyocyte regeneration.…”