Donor Mesenchymal Stromal Cells (MSCs) Undergo Variable Cardiac Reprogramming in Vivo and Predominantly Co-Express Cardiac and Stromal Determinants after Experimental Acute Myocardial Infarction

摘要

We previously showed the emergence of predominantly non-fused murine cells co-expressing cardiac and stromal determinants in co-cultures of murine mesenchymal stromal cells (MSCs) and rat embryonic cardiomyocytes. To determine whether a similar phenotype is detectable in vivo in ischemic myocardium, we infused green fluorescence protein (GFP)-marked MSCs intravenously into wild-type mice in an acute myocardial infarction (AMI) model generated by ischemia/reperfusion (I/R) or fixed coronary artery ligation. We found that infused GFP+ cells were confined strictly to ischemic areas and represented approximately 10 % of total cellularity. We showed that over 60 % of the cells co-expressed collagen type IV and troponin T or myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Nonetheless, up to 25 % of the GFP+ donor cells expressed one of two cardiomyocyte markers, either myosin heavy chain or troponin T, in the absence of MSC determinants. We also observed a marked reduction in OCT4 expression in MSCs pre-infusion compared with those lodged in the myocardium, suggesting reduced stem cell properties. Despite the low frequency of lodged donor MSCs, left-ventricular end-diastolic pressure was significantly better in experimental versus saline animals for both AMI (12.10 ± 1.81 vs. 20.50 ± 1.53 mmHg, p < 0.001) and I/R models (8.75 ± 2.95 vs. 17.53 ± 3.85 mmHg, p = 0.004) when measured 21 days after MSC infusion and is consistent with a paracrine effect. Our data indicate that donor MSCs undergo variable degrees of cardiomyocyte reprogramming with the majority co-expressing cardiomyocyte and stromal markers. Further studies are needed to elucidate the factors mediating the extent of cardiomyocyte reprogramming and importance of the cellular changes on tissue repair.