Role of SDF-1:CXCR4 in Impaired Post-Myocardial Infarction Cardiac Repair in Diabetes

Abstract

Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF‐1:CXCR4 expression is compromised in post‐AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell‐derived factor‐1 (SDF‐1). SDF‐1 expression in control MSC and SDF‐1‐overexpressing MSC (SDF‐1:MSC) were quantified using enzyme‐linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF‐1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF‐1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF‐1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post‐AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post‐AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF‐1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The SDF‐1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of AMI. Over‐express of SDF‐1 expression in diabetes rescues cardiac function post AMI. Our results suggest that modulation of SDF‐1 may improve post‐AMI cardiac repair in diabetes. stem cells translational medicine 2018;7:115–124

Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction

“…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 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 anti‐inflammatory and antiapoptotic effects, as in the current study, our previous studies , and the studies of others . 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.…”

“…In the majority of preclinical and clinical studies , the most commonly used transplantation time window period is within 1 week post‐AMI , although the therapeutic efficacy of MSCs is still weak with only 2%–3% LVEF elevation . It has been reported that SDF‐1/CXCR4 axis plays a paramount role in the recruitment of implanted MSCs for cardiac repair , the natural soaring upregulation of SDF‐1 expression in infarcted myocardium in the early stage (the 1st week) of AMI can recruit more CXCR4‐expressed MSCs , although the severe inflammatory response and oxidative stress may lead to apoptosis and necrosis of the implanted MSCs. On the contrary, in the late stage (the 4th week) of AMI, the inflammation alleviates, making it easier for MSCs to survive, whereas lack of SDF‐1‐driven cell recruitment with scar formation in the infarcted region may impede the potential benefits of MSCs transplantation .…”

“…On the contrary, in the late stage (the 4th week) of AMI, the inflammation alleviates, making it easier for MSCs to survive, whereas lack of SDF‐1‐driven cell recruitment with scar formation in the infarcted region may impede the potential benefits of MSCs transplantation . Many strategies have been investigated to enhance and extend the expression of SDF‐1 , focusing on pharmacological and genetic manipulations like overexpression of SDF‐1 , although only ATV treatment was currently clinical feasible with augmenting SDF‐1 expression, extending its peak expression time from 1 to 7 days and subsiding gradually in 2 weeks post‐AMI . Whether ATV treatment could also increase the SDF‐1 expression in late stage of AMI has not been clarified.…”

SDF‐1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception

“…Indeed, SDF‐1 has been proven to stimulate recruitment of progenitor cells to the ischaemic tissue . SDF‐1 protein levels were increased during the first days after induction of myocardial infarction . Moreover, overexpression of SDF‐1 augmented stem cell homing and incorporation into ischaemic tissues .…”

“…SDF‐1 protein levels were increased during the first days after induction of myocardial infarction . Moreover, overexpression of SDF‐1 augmented stem cell homing and incorporation into ischaemic tissues . Interestingly, hematopoietic stem cells were shown to be exquisitely sensitive to SDF‐1 and did not react to G‐CSF or other chemokines (eg, IL‐8 and RANTES) …”