Cardiac repair and the putative role of stem cells

Stem cell biology has informed and energized cardiac regenerative medicine. The field is linked to a construct that challenges long-standing concepts and advances the basic tenets that: 1) the mammalian heart has the capacity for significant regeneration of cardiomyocytes (CMC) by reentry of CMC into the cell cycle and by activation of endogenous cardiac stem cells and 2) the administration of exogenous stem cell preparations can result in significant myocardial repair and regeneration in cardiac diseases. Based on the latter, major resources have been invested in clinical trials of stem cell therapy. In this review, the cardiac regenerative construct is critically analyzed. This analysis reconfirms the fundamental pathobiological realities that: 1) the mammalian heart behaves as a terminally differentiated organ with limited regenerative capacity and uncertain contribution from endogenous cardiac stem cells, 2) the healing of infarction is by scar formation, and 3) the progression of pathological myocardial remodeling produces heart failure in non-ischemic as well as ischemic disease. Some influential studies underpinning the cardiac regenerative construct now have been called into question. The efficacy of stem cell therapy to produce sustained beneficial effects in patients with ischemic and non-ischemic heart disease remains unproven. It is an open question as to whether new scientific discovery can provide a convincing rationale for further clinical trials of cardiac stem cell therapy. This should be taken into consideration in regulatory review of ongoing and future clinical trials in cardiac regenerative medicine.