Cellular cardiomyoplasty: Evidence of cellular therapy, mechanisms and controversies

Cardiomyocytes are terminally differentiated cells that the heart cannot replace when they are damaged. A couple of decades ago, attempts were made to exogenously replace lost cardiac cells in hope of ultimately avoiding heart failure. However, despite promising initial results, the progress has been humble. One of the main limiting factors has been lack of clear understanding of the mechanism behind the functional improvement observed. Three main hypotheses emerged; the oldest is “trans-differentiation” which assumes that transplanted primitive cells need to differentiate to cardiac cells before contributing to the function. Evidence also supported “fusion”, in which transplanted cells fuse with primitive cardiac cells to improve cardiac function. However, due to the paucity of trans-differentiated or fused cells, it was thought that it was unlikely that these mechanisms are the sole contributors. Evidence has thus emerged that transplanted stem cells actually exert a paracrine effect on the surrounding cells and extracellular matrix with angiogenic, prosurvival and anti-inflammatory effects. In this chapter, we review the evidence behind the mechanisms of functional improvement in “cellular cardiomyoplasty” and carefully investigate the evidence and controversies behind transdifferentiation, fusion and paracrine hypotheses. Evidence from both in-vivo and in-vitro studies is explored.