Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

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.

Inhibition of mitochondrial respiration has fundamentally different effects on proliferation, cell survival and stress response in immature versus differentiated cardiomyocyte cell lines

“…This furthermore raises the question when exactly during cardiomyocyte differentiation the plasticity in orchestrating various cellular stress response mechanisms is lost. Whether this coincides with the loss of cell cycle activity or the switch from glycolysis to an oxidative metabolism after birth (Bongiovanni et al, 2021;Garbern and Lee, 2021) will have to be evaluated in future studies, for example using in vitro differentiation of iPS derived cardiomyocytes. H9c2 cells can be differentiated towards a more cardiomyocyte-like phenotype under defined culture conditions.…”

“…The response of embryonic, fetal or neonatal cardiomyocytes towards mitochondrial dysfunction, however, is less clear. Given that embryonic and neonatal cardiomyocytes can proliferate and allow heart regeneration until the immediate postnatal period (Bongiovanni et al, 2021), it is tempting to speculate that they might also have a higher stress tolerance compared to adult cardiomyocytes. The combination of proliferative potential and a high level of cell protective signaling might equip the pre-and neonatal heart with the best possible plasticity to respond to various insults or pathologies during intrauterine and perinatal growth.…”

Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection

“…These important side effects have been documented for anthracyclines, fluoropyrimidines, and alkylating drugs. This is because lost cardiomyocytes cannot be efficiently regenerated due to the very low ability of the adult mammalian heart to produce new cardiomyocytes (294,295) [reviewed in (296)]. Although the cytotoxic effect of anticancer treatments resides on a wide range of biological mechanisms, the development of strategies aiming at increasing cardiomyocyte survival is thus encouraged to reduce anticancer drug-induced cardiomyocyte death and the consequent permanent damage.…”

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

“…A big problem lies in the inefficient regenerative capacity of the heart. Based on the studies of various animal models as well as human data on cardiac regeneration, the attention has recently shifted toward the possibility of repairing diseased hearts by reawakening the intrinsic regenerative potential (7). The analysis of the integration of 14C generated by nuclear bomb tests during the Cold War allowed to estimate that fewer than 50% of cardiomyocytes are physiologically exchanged during the course of life in the human heart (8), indicating the intrinsic potential of cardiomyocytes renewal in the human myocardium.…”

“…Thus, efforts have been made toward stimulating cardiomyocytes proliferation based on factors responsible for the transient neonatal heart regeneration in animal models. To promote endogenous cardiomyocyte proliferation, initial approaches targeted universal cell cycle regulators such as cyclins, cyclin-dependent kinases (CDKs), tumor suppressor genes, and cell-intrinsic signaling pathways that regulate cardiomyocytes proliferation during development (7,10). These include mainly developmental transcription factors comprising the Hippo, Hedgehog (HH), Wnt pathway, HIF1α, SMADs, TBX20, p53, Jarid2, GATA4, MEIS1/2, Retinoblastoma, PITX2, E2F family members, KLF1, REST (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) as well as chromatin remodeling proteins (26), and microRNAs (miR-590, miR-199a, miR-548c, miR-509, miR-23b, miR-17-92 cluster, miR302-367, miR-143) (27)(28)(29)(30).…”