Single-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation

Yin Wang, Fang Yao, Lipeng Wang, Zheng Li, Zongna Ren, Dandan Li, Mingzhi Zhang, Leng Han, Shi-qiang Wang, Bingying Zhou and Li Wang ()
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Yin Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Fang Yao: Chinese Academy of Medical Sciences and Peking Union Medical College
Lipeng Wang: Peking University
Zheng Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Zongna Ren: Chinese Academy of Medical Sciences and Peking Union Medical College
Dandan Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Mingzhi Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Leng Han: The University of Texas Health Science Center at Houston McGovern Medical School
Shi-qiang Wang: Peking University
Bingying Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College
Li Wang: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. By integrating single-cell RNA-sequencing data of mouse hearts at multiple postnatal stages, we construct cellular interactomes and regulatory signaling networks. Here we report switching of fibroblast subtypes from a neonatal to adult state and this drives cardiomyocyte maturation. Molecular and functional maturation of neonatal mouse cardiomyocytes and human embryonic stem cell-derived cardiomyocytes are considerably enhanced upon co-culture with corresponding adult cardiac fibroblasts. Further, single-cell analysis of in vivo and in vitro cardiomyocyte maturation trajectories identify highly conserved signaling pathways, pharmacological targeting of which substantially delays cardiomyocyte maturation in postnatal hearts, and markedly enhances cardiomyocyte proliferation and improves cardiac function in infarcted hearts. Together, we identify cardiac fibroblasts as a key constituent in the microenvironment promoting cardiomyocyte maturation, providing insights into how the manipulation of cardiomyocyte maturity may impact on disease development and regeneration.

Date: 2020
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DOI: 10.1038/s41467-020-16204-w

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