10. Human Mesenchymal Stem Cell (hMSC) Delivery System Induces Favorable Post-Infarct Cardiac Remodeling with an Increase in Coronary Artery Blood Flow

Abstract

[Background] Myocardial infarction (MI) caused by coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. We are at a crucial juncture where novel therapeutic approaches for reversing adverse cardiac remodeling are solely needed. The beneficial effects of multipotent mesenchymal stem cells (MSCs) are primarily mediated via combined paracrine, endocrine, and homing actions. Human MSCs are one of the best candidates for inducing favorable cardiac remodeling after MI. Recently, we constructed porous PLGA/PEI1.8k biodegradable microspheres (PPP) for the delivery of hMSCs using electrostatic attraction and structural entrapment. These MSC–loaded PPP particles showed increased in vivo engraftment rates and maintained better stemness characteristics of hMSCs in comparison with hMSCs–alone in rats 2 wks after intramyocardial injections.[Aim] We hypothesized that human MSCs delivered with a biocompatible porous scaffold would produce cardio-protective effects on post-infarct cardiac remodeling.[Results] hMSCs–alone and PPP loaded with 3 different amounts of hMSC (High, Medium, and Low) demonstrated improved systolic function and preserved cardiac geometry compared with ischemia-reperfusion (I-R) group in rats 1 wk after post-infarct intramyocardial administration. The functional improvement of hMSC–loaded PPP groups was sustained 4 wks after MI and comparable between groups. However, the hMSCs–alone group didn't maintain functional improvement. The functional improvement of hMSC–loaded PPP groups was supported by reduced infarct size, ameliorated cardiac fibrosis, protection from cardiomyocyte loss, and decreased apoptotic activity. Also, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the cardio-protective effects of hMSC–loaded PPP. Interestingly, hMSC–loaded PPP groups enhanced blood flow of infarct-related coronary artery.[Conclusion] These results suggest that an hMSC–loaded PPP delivery system would provide amplification and decrease costs of hMSC therapy, especially in ex vivo preparation.