Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

Miao Cui,Miao Cui,Maria Gabriela Morales,Xue Xiao,Ayhan Atmanli,Wei Tan,Ayhan Atmanli,Ning Liu,Ning Liu,Eric N Olson,Eric N Olson,Kenian Chen,Rhonda Bassel-Duby,Rhonda Bassel-Duby,Wei Tan,Lin Xu,Maria Gabriela Morales

doi:10.1038/s41467-021-25653-w

Abstract

Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.

Highlights

IntroductionThe mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined
Following injury, cells in regenerative tissues have the ability to regrow
This group of high Acta2-expressing cardiomyocytes was not detected in nonregenerative hearts at P8 (Fig. 1c, d), validating our previous observation that CM4 cells disappear as the heart loses its ability to regenerate[5]

Summary

Introduction

The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Our findings reveal that the adaptive stress response mechanism mediated by Nrf[1] is required for neonatal heart regeneration and confers cardioprotection in the adult heart. SnRNA-seq revealed that genetic deletion of Nrf[1] prevented neonatal cardiomyocytes from activating a transcriptional program required for heart regeneration. Our study uncovers a unique adaptive mechanism activated in response to injury that maintains the tissue homeostatic balance required for heart regeneration. Reactivating this mechanism in the adult heart represents a potential therapeutic approach for cardiac repair

Methods

Results

Conclusion