Bongiovanni Chiara, Sacchi Francesca, Da Pra Silvia, Pantano Elvira, Miano Carmen, Morelli Marco Bruno, D'Uva Gabriele
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.
Front Cardiovasc Med. 2021 Oct 8;8:750604. doi: 10.3389/fcvm.2021.750604. eCollection 2021.
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.
尽管为开发基于干细胞/祖细胞的技术付出了巨大努力，旨在严重损伤后替代和恢复心脏组织，但迄今为止，尚未证明基于成体干细胞移植的策略能够有效地产生新的心肌细胞。有趣的是，已存在的心肌细胞的去分化和增殖而非干细胞分化是低等脊椎动物自发再生受损心脏的主要细胞机制。哺乳动物在新生儿早期也能够再生心脏，即便在这种情况下也是通过激活内源性心肌细胞的增殖来实现。然而，哺乳动物的心脏再生潜力在出生后不久就会急剧下降，此时大多数心肌细胞退出细胞周期，进一步成熟，并继续增大尺寸。尽管在成年哺乳动物（包括小鼠和人类）中也记录到心肌细胞有缓慢的更新率，但这不足以维持强大的再生过程。尽管如此，这些显著的发现为一系列新型再生方法打开了大门，这些方法旨在通过触发内源性心肌细胞的部分去分化过程和重新进入细胞周期来重新激活内源性心脏再生潜力。从出生开始并持续到新生儿早期，从子宫内到子宫外生活的一系列适应性变化共同导致了哺乳动物心脏再生能力的丧失。已证明多种全身和微环境因素或细胞内在分子参与者可调节心肌细胞增殖，并且对它们的操控已被探索作为一种治疗策略，以促进损伤后心脏功能的恢复。我们在此回顾了在这个新颖且蓬勃发展的研究领域中迄今所获得的科学知识，阐明了关键的生物学和分子机制，对其进行调节可能是再生人类受损心肌的一种可行方法。
