Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.

Rationale: Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective: The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results: We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions: Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration.研究背景：新生小鼠在心脏遭受损伤时具备心肌再生能力，但该再生潜能在出生后第一周即会丧失。目前，哺乳动物心脏再生背后的转录调控变化尚未在分子层面得到完整解析。 研究目的：本研究旨在明确心肌细胞在再生过程中是否会将转录表型逆转至更低分化状态，并系统分析转录组数据，以鉴定并验证该过程的潜在调控因子。 方法与结果：通过对比体外与体内心肌细胞分化动态模型、体外心肌细胞外植模型以及新生小鼠心脏切除模型中的全局转录程序，我们构建了小鼠损伤诱导心肌细胞再生的核心转录特征。再生中的小鼠心脏展现出心肌细胞分化进程的转录逆转现象，包括重新激活潜在的发育程序，这与外植模型中成熟心肌细胞表型去稳定时观察到的特征高度相似。我们鉴定出核心调控网络的潜在上游调控因子，包括白细胞介素13（interleukin 13, IL13），其可在体外诱导心肌细胞进入细胞周期并激活STAT6/STAT3信号通路。研究证实，STAT3/骨膜蛋白（periostin）与STAT6信号通路是IL13在心肌细胞中发挥调控作用的关键介质，这些下游信号分子在再生小鼠心脏中同样受到调控。 结论：本研究揭示了哺乳动物心脏再生转录调控的全新机制，为筛选可促进心脏再生的潜在调控因子提供了核心研究框架。