Undeniable Evidence That the Adult Mammalian Heart Lacks an Endogenous Regenerative Stem Cell

Over the past 2 decades, reports of adult stem cells serving as mediators of cardiac regeneration of infarcted tissue have been a source of great hope in cardiovascular medicine. One of the most highly touted adult stem cell types was defined by expression of the cell surface receptor c-Kit, which in bone marrow marks the known hematopoietic progenitors that give rise to all immune and blood cells. With respect to the heart, publications in the early 2000s showed that injection of c-Kit+ cells, either bone marrow derived or derived from within the heart itself, was able to regenerate up to ≈70% of the infarcted rodent myocardium when injected into the injured area.1,2 Although independent laboratories were unable to replicate these early findings,3–5 the field nonetheless moved quickly to the clinic with an array of human trials, starting with bone marrow mononuclear cells and followed thereafter with expanded autologous cardiac stem cells or mesenchymal stem cells from various sources. Collective evidence from these trials has demonstrated that “adult stem cell” injection is largely safe in patients but that efficacy remains unclear, with some trials failing to meet primary end points.5 None of these injected cell types have demonstrated an ability to engraft and directly generate new myocardium in clinical applications, and today, the preponderance of recent evidence in rodent models fails to demonstrate physiologically relevant new cardiomyocyte generation with injection of any sort of presumed adult stem cell.6,7 The assertion that the heart contains its own dedicated cardiomyocyte-producing stem cell is absolutely central to the entire cardiac regeneration–stem cell debate. If the heart truly lacks such an endogenous adult stem cell, this calls into question previous studies in which cardiac regeneration was reported such as from c-Kit+ cells isolated from the heart, selected, expanded, and reinjected back into the circulation, where they then homed to the heart and created new myocardium.6 Indeed, the US Food and Drug Administration recently summarized the state of affairs surrounding stem cell therapy for indications such as heart failure as follows: