Single-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation
Single-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation
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小鼠成纤维细胞的单细胞分析确定了调节心肌细胞成熟的新生儿到成人的转换
DOI：
10.1038/s41467-020-16204-w
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发表时间：
2020-05-22
影响因子：
16.6
通讯作者：
Wang, Li
中科院分区：
文献类型：
--
作者：
Wang, Yin;Yao, Fang;Wang, Li
心脏成熟为出生后心脏发育和疾病奠定了基础，但人们对微环境对心肌细胞成熟的贡献知之甚少。通过整合小鼠心脏在多个出生后阶段的单细胞 RNA 测序数据，我们构建了细胞相互作用组和调控信号网络。在这里，我们报告了成纤维细胞亚型从新生儿状态到成人状态的转变，这推动了心肌细胞的成熟。与相应的成年心脏成纤维细胞共培养后，新生小鼠心肌细胞和人胚胎干细胞衍生的心肌细胞的分子和功能成熟显着增强。此外，体内和体外心肌细胞成熟轨迹的单细胞分析确定了高度保守的信号通路，其药理学靶向显着延迟出生后心脏中的心肌细胞成熟，并显着增强心肌细胞增殖并改善梗塞心脏中的心脏功能。我们共同确定心脏成纤维细胞是促进心肌细胞成熟的微环境中的关键成分，从而深入了解心肌细胞成熟度的操纵如何影响疾病的发展和再生。
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.