Optimizing Cell-Based Therapy for Cardiac Regeneration

Abstract

Long thought to be a terminally differentiated organ, recent findings suggest that the adult mammalian heart is a slowly regenerating organ1 and home to a resident population of cardiac progenitor cells (CPCs) that renew cardiomyocytes and have the potential to differentiate into multiple cell types within the myocardium.2 In spite of this, the regenerative capacity of the mammalian heart is inadequate compared with the resulting damage caused by ischemic episodes. In light of the challenges faced by resident progenitor cells, many studies have focused on delivery of exogenously prepared stem or progenitor cell types to the damaged heart. CPCs are an ideal candidate for cardiac cell-based therapy because they are programmed to differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells, thus providing not only contractile benefit but also increased vascularization. However, the ischemic myocardium is a hostile microenvironment, and multiple factors contribute to prevent cardiac regeneration, including ischemia, inflammation, and fibrosis. Therefore, it is critical to provide a complementary approach that promotes CPC survival, proliferation, and differentiation. Article see p 876 In the study by Padin-Iruegas et al3 in this issue of Circulation , insulin-like growth factor 1 (IGF-1), an endogenous peptide that is activated in response to cardiac injury,4 is delivered to the heart using nanofiber tethering (NF-IGF-1) both alone and in combination with CPCs. In vivo administration of CPCs plus NF-IGF-1 led to significantly more CPC-derived cardiomyocytes that were larger, more differentiated, and incorporated electrically and mechanically into the host myocardium. This combination treatment also increased endogenous CPC proliferation and differentiation to cardiomyocytes, endothelial cells, and smooth muscle cells. Combination therapy led to significant improvement in both ventricular performance and morphological parameters compared with CPC or NF-IGF-1 treatment alone, emphasizing the therapeutic benefit of prolonged exposure of CPCs to IGF-1. One of the …