Yücel Dogacan, Garay Bayardo I, Perlingeiro Rita C R, van Berlo Jop H
Department of Medicine, Lillehei Heart Institute, Cardiovascular Division, University of Minnesota, Minneapolis, MN, United States.
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, United States.
Front Cell Dev Biol. 2022 May 19;10:806564. doi: 10.3389/fcell.2022.806564. eCollection 2022.
The heart is one of the least regenerative organs. This is in large part due to the inability of adult mammalian cardiomyocytes to proliferate and divide. In recent years, a number of small molecules and molecular targets have been identified to stimulate cardiomyocyte proliferation, including p38 inhibition, YAP-Tead activation, fibroblast growth factor 1 and Neuregulin 1. Despite these exciting initial findings, a therapeutic approach to enhance cardiomyocyte proliferation is still lacking. We hypothesized that a more comprehensive validation using live-cell imaging and assessment of the proliferative effects on various cardiomyocyte sources might identify the most potent proliferative stimuli. Here, we used previously published stimuli to determine their proliferative effect on cardiomyocytes from different species and isolated from different developmental timepoints. Although all stimuli enhanced DNA synthesis and Histone H3 phosphorylation in neonatal rat ventricular cardiomyocytes to similar degrees, these effects varied substantially in mouse cardiomyocytes and human iPSC-derived cardiomyocytes. Our results highlight p21 inhibition and Yap-Tead activation as potent proliferative strategies to induce cultured cardiomyocyte cell cycle activity across mouse, rat and human cardiomyocytes.
心脏是再生能力最差的器官之一。这在很大程度上是由于成年哺乳动物的心肌细胞无法增殖和分裂。近年来，已鉴定出多种小分子和分子靶点来刺激心肌细胞增殖，包括抑制p38、激活YAP-Tead、成纤维细胞生长因子1和神经调节蛋白1。尽管有这些令人兴奋的初步发现，但仍缺乏增强心肌细胞增殖的治疗方法。我们推测，使用活细胞成像进行更全面的验证以及评估对各种心肌细胞来源的增殖作用，可能会确定最有效的增殖刺激因素。在此，我们使用先前发表的刺激因素来确定它们对来自不同物种且从不同发育时间点分离的心肌细胞的增殖作用。尽管所有刺激因素都能使新生大鼠心室心肌细胞中的DNA合成和组蛋白H3磷酸化程度相似地增强，但这些作用在小鼠心肌细胞和人诱导多能干细胞衍生的心肌细胞中差异很大。我们的结果突出了抑制p21和激活Yap-Tead作为诱导小鼠、大鼠和人心肌细胞培养物细胞周期活性的有效增殖策略。
