Abstract
Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.
Highlights
Specialty section: This article was submitted to Cardiovascular Biologics and Regenerative Medicine, a section of the journal Frontiers in Cardiovascular Medicine
None of these treatments can reverse the progression of the disease or cope with the underlying conspicuous loss of cardiac muscle cells that are replaced by fibrotic scar tissue
A population of lineage negative c-kit+ cardiac stem cells was initially reported to give rise to all major cardiac cell types, including cardiomyocytes [4], more recent lineage tracing studies based on tamoxifen-inducible CreLoxP technology unveiled that newly cardiomyocytes generated from c-kit+ cells are extremely rare, irrelevant in terms of cardiomyocyte regeneration, despite abundantly contributing to the generation of endothelial cells [5] [reviewed by Passier and colleagues [6] and Chien and colleagues [7]]
Summary
TOWARD THE DIRECT STIMULATION OF CARDIOMYOCYTE PROLIFERATION FOR HEART REGENERATION. Heart failure, consisting in the inability of the heart to pump enough blood to meet the body’s needs, is a prominent cause of death worldwide and often occurs as a result of severe cardiac injuries, such as those induced by myocardial infarction [reviewed by Savarese and colleagues [1]]. Besides left ventricular assist devices and heart transplant, which is the most curative approach, yet with severe limitations (scarcity of donors, extremely high costs, immune response, and organ rejection, etc.), currently available therapies are mainly based on pharmacological treatments for slowing down disease progression and reducing symptoms None of these treatments can reverse the progression of the disease or cope with the underlying conspicuous loss of cardiac muscle cells (cardiomyocytes) that are replaced by fibrotic scar tissue. Myocardial infarction in 1 or 2-days-old swine, is followed by cardiac tissue replacement achieved by dedifferentiation and proliferation of pre-existing cardiomyocytes in the border zone [19, 20] It has been reported the astonishing clinical case of a newborn child undergoing a rapid functional cardiac recovery after myocardial infarction, it was not possible to assess if the observed recovery was due to bona fide regeneration or reversible functional impairment [21]. We review the major changes occurring at birth and in the immediate postnatal period, along with systemic, micro-environmental, intracellular stimuli influencing the proliferative ability of endogenous cardiomyocytes, whose manipulation is a promise for enhancing cardiomyocyte regeneration and boosting cardiac function in heart failure patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
