What is it about?
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.
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Why is it important?
The field of cell-based therapy for cardiac regeneration is based on the tenuous premise that therapy with various stem cell preparations can overcome the intrinsic biological properties of the mammalian myocardium and lead to significant myocardial regeneration and sustained functional improvement following acute or chronic injury. In spite of an increasingly tenuous regenerative cardiac construct, millions of dollars have been expended on clinical trials of cardiac stem cell therapy. These clinical trials have yielded unconvincing results regarding the efficacy of stem cell therapy to produce sustained improvement of cardiac structure and function in patients with ischemic and non-ischemic heart disease. The research community now must address the fundamental issue of whether further investment of human and financial resources in cell-based therapy for cardiac diseases is worth the modest cardiac functional improvement, which may or may not be sustainable, versus other forms of therapy.
Perspectives
The capability for myocardial regeneration of various putative cardiac precursor cell populations, i.e. the “stemness” of these populations, should be regarded as negligible unless proven otherwise. Embryonic and iPSCs are exceptions since they have been shown to retain their ability to differentiate into cardiomyocytes. But multiple issues with the use of stem cell-derived cardiomyocyte grafts, including arrhythmia development, remain to be worked out. More basic investigation is needed to determine mechanisms to account for the paradoxical effect of modest functional improvement without myocardial remuscularization observed with most forms of cell-based therapy.Rigorous regulatory review is imperative to clarify the scientific rationale and justification for continuation of ongoing clinical trials and the initiation of future clinical trials in cardiac regenerative medicine.
Dr. Louis Maximilian Buja
McGovern Medical School, The University of Texas Health Science Center at Houston
Read the Original
This page is a summary of: Cardiac repair and the putative role of stem cells, Journal of Molecular and Cellular Cardiology, March 2019, Elsevier,
DOI: 10.1016/j.yjmcc.2019.01.022.
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