Dynamic Transcriptional Responses to Injury of Regenerative and Non-regenerative Cardiomyocytes Revealed by Single-Nucleus RNA Sequencing

Miao Cui, Zhaoning Wang, Kenian Chen, Akansha M. Shah, Wei Tan, Lauren Duan, Efrain Sanchez-Ortiz, Hui Li, Lin Xu, Ning Liu, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart can efficiently regenerate during the first week of life. The molecular mechanisms that mediate the regenerative response and its blockade in later life are not understood. Here, by single-nucleus RNA sequencing, we map the dynamic transcriptional landscape of five distinct cardiomyocyte populations in healthy, injured, and regenerating mouse hearts. We identify immature cardiomyocytes that enter the cell cycle following injury and disappear as the heart loses the ability to regenerate. These proliferative neonatal cardiomyocytes display a unique transcriptional program dependent on nuclear transcription factor Y subunit alpha (NFYa) and nuclear factor erythroid 2-like 1 (NFE2L1) transcription factors, which exert proliferative and protective functions, respectively. Cardiac overexpression of these two factors conferred protection against ischemic injury in mature mouse hearts that were otherwise non-regenerative. These findings advance our understanding of the cellular basis of neonatal heart regeneration and reveal a transcriptional landscape for heart repair following injury.

Original languageEnglish (US)
Pages (from-to)102-116.e8
JournalDevelopmental cell
Volume53
Issue number1
DOIs
StatePublished - Apr 6 2020

Keywords

  • NFE2L1
  • NFYa
  • cell survival
  • heart regeneration
  • ischemia
  • transcriptional response to injury

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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