Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [scRNA-Seq]

Heart disease can be caused by ischemic coronary artery injury, hypertension, and chemotherapy, all of which lead to loss or dysfunction of cardiac muscle. The adult mammalian heart lacks the ability to regenerate. In contrast, the heart of neonatal mice, within the first week after birth, possesses a unique ability to regenerate lost myocardium following injury, mediated by proliferation of cardiomyocytes. The mechanisms whereby neonatal cardiomyocytes adapt to injury-induced stress conditions and activate regenerative cellular programs remain to be defined. Here, we show that Nrf1, an endoplasmic reticulum (ER) bound transcription factor, is expressed in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented cardiomyocytes from activating a transcriptional program required for heart regeneration, revealed by single-nucleus RNA sequencing (snRNA-seq). Conversely, adeno-associated virial (AAV) overexpression of Nrf1 protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) from doxorubicin-induced cardiotoxicity. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal a mechanistic interplay between adaptive stress responses and heart regeneration, and highlight the central role of Nrf1 in these processes.

缺血性冠状动脉损伤、高血压与化疗均可诱发心脏疾病，上述致病因素均会导致心肌丢失或功能异常。成年哺乳动物心脏缺乏再生能力。与之相反，新生小鼠在出生后一周内的心脏，可通过心肌细胞增殖介导损伤后丢失的心肌组织再生，这是其独特的再生潜能。目前，新生心肌细胞如何适应损伤诱导的应激环境、激活再生细胞程序的具体机制仍有待阐明。本研究发现，定位于内质网（endoplasmic reticulum, ER）的转录因子Nrf1在再生心肌细胞中表达。通过单细胞核RNA测序（single-nucleus RNA sequencing, snRNA-seq）分析显示，敲除Nrf1会阻止心肌细胞激活心脏再生所需的转录程序。反之，腺相关病毒（adeno-associated viral, AAV）介导的Nrf1过表达可保护成年小鼠心脏免受缺血再灌注（ischemia/reperfusion, I/R）损伤。此外，Nrf1还可保护人类诱导多能干细胞衍生心肌细胞（human induced pluripotent stem cell-derived cardiomyocytes, hPSC-CMs）免受阿霉素诱导的心肌毒性。Nrf1的保护功能通过涉及蛋白酶体激活与氧化还原稳态的双重应激响应机制实现。本研究揭示了适应性应激响应与心脏再生之间的机制性互作，并凸显了Nrf1在上述过程中的核心作用。