Chapter 21 - Basic pathobiology of cell-based therapies and cardiac regenerative medicine

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Abstract

Stem cell biology has informed and energized cardiac regenerative medicine. The rationale for the field is based on observations that challenge previously accepted concepts and advance the basic tenets that: (1) the mammalian heart has the capacity for significant regeneration of cardiomyocytes (CMC) by activation of endogenous cardiac stem cells along with reentry of CMC into the cell cycle and (2) the administration of exogenous stem cell preparations can bolster the intrinsic cardiac regenerative capacity, resulting in significant myocardial repair and regeneration. Based on these assertions, major resources have been invested in clinical trials of stem cell therapy. In this chapter, the cardiac regenerative construct is critically analyzed. This analysis reconfirms the fundamental pathobiological reality that the mature mammalian heart behaves as a terminally differentiated organ with a very low rate of turnover of CMC and a limited regenerative capacity. Adult stem cells derived from bone marrow or heart cannot repopulate myocardium, and any beneficial outcomes are limited to paracrine effects. CMC derived from pluripotent stem cells (PSCs), either embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSC), have the ability to engraft to the myocardium but immunogenicity and arrhythmogenesis are current impediments to clinical application. The efficacy of stem cell therapy to produce sustained beneficial effects in patients with ischemic and nonischemic heart disease through myocardial repair or regeneration remains unproven. Further clinical trials of cardiac stem cell therapy must meet rigorous scientific and regulatory standards. Alternative approaches to myocardial repair and regeneration merit further consideration, including developing agents and approaches to modulate CMC terminal differentiation.

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