Integrin α4 Positive Subpopulation in Adipose Derived Stem Cells Effectively Reduces Infarct Size through Enhanced Engraftment into Myocardial Infarction.

Abstract

The efficacy of adipose-derived stem cells (ASCs) on myocardial infarction is limited due to poor survival and engraftment. Integrin-mediated cell adhesion is a prerequisite for its survival and homing. ASCs expressed insufficient integrin α₄, limiting their homing capacity. This study aims to characterize integrin α₄^＋ ASC subpopulation and investigate their therapeutic efficacy in myocardial infarction. We used fluorescence-activated cell sorting to harvest integrin α₄^＋ ASCs subpopulation, which were characterized in vitro and transplanted into myocardial infarction model. Positron emission tomography imaging were performed to measure infarction size. Cardiac cine magnetic resonance imaging was used to evaluate heart contractile function. Compared with the unfractionated ASCs, integrin α₄^＋ ASCs subpopulation secreted a higher level of angiogenic growth factors, migrated more rapidly, and exhibited a stronger anti-apoptotic capacity. Vascular cell adhesion molecule-1 was obviously up-regulated at 3 days after myocardial infarction, which interacted with integrin α₄ receptor on the surface of ASCs to enhance the survival and adhesion. Thus, we implanted unfractionated ASCs or integrin α₄^＋ ASCs subpopulation into the 3-day infarcted myocardium. Integrin α₄^＋ ASCs subpopulation exhibited more robust engraftment into the infarcted myocardium. Integrin α₄^＋ ASCs subpopulation more effectively decreased infarct size and strengthen cardiac function recovery than did the unfractionated ASCs. Integrin α₄^＋ ASCs subpopulation is superior to unfractionated ASCs in ameliorating ischemic myocardial damage in animal model. Mechanistically, their more robust engraftment into the infarct area, higher migratory capacity and their increased release of paracrine factors contribute to enhanced tissue repair.