@article{7af7561031d3421f8b6ae1db1e2f059a,
title = "Dynamic Transcriptional Responses to Injury of Regenerative and Non-regenerative Cardiomyocytes Revealed by Single-Nucleus RNA Sequencing",
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.",
keywords = "NFE2L1, NFYa, cell survival, heart regeneration, ischemia, transcriptional response to injury",
author = "Miao Cui and Zhaoning Wang and Kenian Chen and Shah, {Akansha M.} and Wei Tan and Lauren Duan and Efrain Sanchez-Ortiz and Hui Li and Lin Xu and Ning Liu and Rhonda Bassel-Duby and Olson, {Eric N.}",
note = "Funding Information: We thank Jose Cabrera for graphics; Drs. Jian Xu, Xin Liu, and Yoon Jung Kim from the Children's Research Institute at the University of Texas Southwestern Medical Center for performing the Illumina sequencing;Dr. Xiang Luo for help with isolating neonatal rat ventricular cardiomyocytes; John Shelton from the Molecular Histopathology Core for help with histology; and Dr. Stephen Hauschka for the CK8e promoter used for AAV. This work was supported by grants from the NIH (AR-067294, HL-130253, HL-138426, and HD-087351), the Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular Research, and the Robert A. Welch Foundation (grant 1-0025 to E.N.O.). Z.W. was supported by a predoctoral fellowship from the American Heart Association and the Harry S. Moss Heart Trust (19PRE34380436). M.C. Z.W. W.T. A.M.S. L.D. E.S.-O. and H.L. designed and performed experiments; M.C. K.C. and Z.W. performed the data analysis; L.X. and N.L. contributed to discussion; M.C. R.B.-D. and E.N.O. wrote the manuscript. The authors declare no competing interests. Funding Information: We thank Jose Cabrera for graphics; Drs. Jian Xu, Xin Liu, and Yoon Jung Kim from the Children{\textquoteright}s Research Institute at the University of Texas Southwestern Medical Center for performing the Illumina sequencing;Dr. Xiang Luo for help with isolating neonatal rat ventricular cardiomyocytes; John Shelton from the Molecular Histopathology Core for help with histology; and Dr. Stephen Hauschka for the CK8e promoter used for AAV. This work was supported by grants from the NIH ( AR-067294 , HL-130253 , HL-138426 , and HD-087351 ), the Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular Research, and the Robert A. Welch Foundation (grant 1-0025 to E.N.O.). Z.W. was supported by a predoctoral fellowship from the American Heart Association and the Harry S. Moss Heart Trust ( 19PRE34380436 ). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "6",
doi = "10.1016/j.devcel.2020.02.019",
language = "English (US)",
volume = "53",
pages = "102--116.e8",
journal = "Developmental cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "1",
}