Department of Cell Biology, Duke University, Durham, United States.
Department of Biomedical Engineering, Duke University, Durham, United States.
Elife. 2021 Oct 19;10:e65512. doi: 10.7554/eLife.65512.
Multiple mitogenic pathways capable of promoting mammalian cardiomyocyte (CM) proliferation have been identified as potential candidates for functional heart repair following myocardial infarction. However, it is unclear whether the effects of these mitogens are species-specific and how they directly compare in the same cardiac setting. Here, we examined how CM-specific lentiviral expression of various candidate mitogens affects human induced pluripotent stem cell-derived CMs (hiPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) in vitro. In 2D-cultured CMs from both species, and in highly mature 3D-engineered cardiac tissues generated from NRVMs, a constitutively active mutant form of the human gene Erbb2 (cahErbb2) was the most potent tested mitogen. Persistent expression of cahErbb2 induced CM proliferation, sarcomere loss, and remodeling of tissue structure and function, which were attenuated by small molecule inhibitors of Erk signaling. These results suggest transient activation of Erbb2/Erk axis in CMs as a potential strategy for regenerative heart repair.
已经确定了多种有丝分裂原途径，它们能够促进哺乳动物心肌细胞（CM）的增殖，是心肌梗死后功能性心脏修复的潜在候选方法。然而，目前尚不清楚这些有丝分裂原的作用是否具有物种特异性，以及它们在相同的心脏环境中如何直接比较。在这里，我们研究了各种候选有丝分裂原的 CM 特异性慢病毒表达如何影响体外人诱导多能干细胞衍生的 CM（hiPSC-CM）和新生大鼠心室肌细胞（NRVM）。在两种物种的 2D 培养的 CM 中，以及从 NRVM 产生的高度成熟的 3D 工程化心脏组织中，人基因 Erbb2 的一种组成型激活突变体（cahErbb2）是测试的最有效有丝分裂原。cahErbb2 的持续表达诱导 CM 增殖、肌节丧失以及组织结构和功能的重塑，Erk 信号的小分子抑制剂可减弱这些作用。这些结果表明，CM 中 Erbb2/Erk 轴的短暂激活可能是再生心脏修复的一种潜在策略。
