Molecular basis of functional myogenic specification of Bona Fide multipotent adult cardiac stem cells

Apr 10, 2025

ABSTRACT

Ischemic Heart Disease (IHD) remains the developed world’s number one killer. The improved survival from Acute Myocardial Infarction (AMI) and the progressive aging of western population brought to an increased incidence of chronic Heart Failure (HF), which assumed epidemic proportions nowadays. Except for heart transplantation, all treatments for HF should be considered palliative because none of the current therapies can reverse myocardial degeneration responsible for HF syndrome. To stop the HF epidemic will ultimately require protocols to reduce the progressive cardiomyocyte (CM) loss and to foster their regeneration. It is now generally accepted that mammalian CMs renew throughout life. However, this endogenous regenerative reservoir is insufficient to repair the extensive damage produced by AMI/IHD while the source and degree of CM turnover remains strongly disputed. Independent groups have convincingly shown that the adult myocardium harbors bona-fide tissue specific cardiac stem cells (CSCs). Unfortunately, recent reports have challenged the identity and the endogenous myogenic capacity of the c-kit expressing CSCs. This has hampered progress and unless this conflict is settled, clinical tests of repair/regenerative protocols are unlikely to provide convincing answers about their clinical potential. Here we review recent data that have eventually clarified the specific phenotypic identity of true multipotent CSCs. These cells when coaxed by embryonic cardiac morphogens undergo a precisely orchestrated myogenic commitment process robustly generating bona-fide functional cardiomyocytes. These data should set the path for the revival of further investigation untangling the regenerative biology of adult CSCs to harness their potential for HF prevention and treatment.

KEYWORDS: Cardiac stem cells, myogenic differentiation, cardiac regeneration

Introduction

Cardiovascular diseases (CVD) are the number one cause of mortality worldwide with an estimated 17.3 million deceases per year representing 31.5% of all global deaths [1]. The most important CVD, in terms of mortality, morbidity and average life expectancy, is myocardial infarction (MI). In response to cardiomyocyte (CM) loss by MI, the heart tries to compensate the lost muscle mass with pathological cardiac remodelling [2]. The latter entails reactive CM hypertrophy, ongoing cell death and replacement fibrosis, which produce a diseased myocardial milieu that impairs regeneration events [3,4], leading over time to heart failure (HF), a chronic and progressive condition in which the heart fails to sustain appropriate organs’ blood supply. Despite all novel and current pharmacological treatments [5], there is no curative treatment for chronic HF that has now reached epidemic proportions and for which a global call to action has been launched to find an effective, affordable and widely available therapy.

During physiological mammalian growth, approximately 40% of all adult CMs are generated in neonatal life; after this period and during early adulthood, cardiac growth is characterized by a transition from a hyperplastic to a hypertrophic phase, with formation of bi-nucleated CMs that permanently withdraw from the cell cycle, becoming terminally differentiated cells [6,7]. However, the adult heart maintains a constant CM turnover rate, the amount of which has been extrapolated to be less than 1% per year whereby this extrapolation is based on mathematical formulas and not on actual direct counting. Independently from the real CM turnover rate, it remains indisputable that CM loss by myocardial ischemia and infarction are not adequately refreshed by new endogenous CM formation, that is insufficient to prevent heart failure [8–10]. Considering the decrease in the number of viable CMs after injury, associated with the (mala)adaptive hypertrophy of the remaining CMs that inefficiently perform their specialized function [11], heart transplantation is the only therapeutic option to revert HF, despite all biological limitation, post-surgery problems and complications of cardiac transplant together with the severe shortage of donors compared to the increasing number of HF patients in need of organ transplantation.

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