Transcriptome profiling of neonatal rat ventricular cardiomyocytes overexpressing NFYa or NFE2L1

The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart has a transient ability to regenerate, however the molecular mechanism that mediates this regenerative response is not fully understood. Here, by single-nucleus RNA sequencing we map the transcriptome landscape of cardiomyocytes in neonatal mouse hearts at healthy, regenerative, and remodeling conditions. We show that an immature cardiomyocyte population enters cell-cycle in response to injury. Absence of this cardiomyocyte population overtime is associated with the loss of the ability of the heart to regenerate. We show a defined injury response in these cardiomyocytes, including activation of transcription factors NFYa and NFE2L1, which play proliferative and protective roles, respectively. We further show that overexpression of these two factors in vivo promotes heart regeneration. Thus, these findings refined our understanding of cellular basis of neonatal heart regeneration and reveal dynamic transcriptome landscape of cardiomyocytes in response to injury.成年哺乳动物心脏在损伤后无法实现再生。与之形成对比的是，新生小鼠心脏具有一过性的再生能力，但其介导该再生反应的分子机制尚未完全阐明。本研究通过单细胞核RNA测序（single-nucleus RNA sequencing），绘制了健康状态、再生状态及重塑状态下新生小鼠心脏心肌细胞的转录组图谱。研究发现，未成熟心肌细胞群体可响应损伤进入细胞周期。随着时间推移，该心肌细胞群体的缺失与心脏再生能力的丧失相关。我们还在这类心肌细胞中发现了明确的损伤应答反应，包括转录因子NFYa与NFE2L1的激活——二者分别发挥增殖与保护作用。进一步实验表明，在体内过表达这两种因子可促进心脏再生。综上，本研究完善了我们对新生心脏再生细胞基础的理解，并揭示了心肌细胞响应损伤时的动态转录组图谱。