Distinct mononuclear diploid cardiac subpopulation with minimal cell–cell communications persists in embryonic and adult mammalian heart

Abstract

A small proportion of mononuclear diploid cardiomyocytes (MNDCMs), with regeneration potential, could persist in adult mammalian heart. However, the heterogeneity of MNDCMs and changes during development remains to be illuminated. To this end, 12 645 cardiac cells were generated from embryonic day 17.5 and postnatal days 2 and 8 mice by single-cell RNA sequencing. Three cardiac developmental paths were identified: two switching to cardiomyocytes (CM) maturation with close CM–fibroblast (FB) communications and one maintaining MNDCM status with least CM–FB communications. Proliferative MNDCMs having interactions with macrophages and non-proliferative MNDCMs (non-pMNDCMs) with minimal cell–cell communications were identified in the third path. The non-pMNDCMs possessed distinct properties: the lowest mitochondrial metabolisms, the highest glycolysis, and high expression of Myl4 and Tnni1. Single-nucleus RNA sequencing and immunohistochemical staining further proved that the Myl4⁺Tnni1⁺ MNDCMs persisted in embryonic and adult hearts. These MNDCMs were mapped to the heart by integrating the spatial and single-cell transcriptomic data. In conclusion, a novel non-pMNDCM subpopulation with minimal cell–cell communications was unveiled, highlighting the importance of microenvironment contribution to CM fate during maturation. These findings could improve the understanding of MNDCM heterogeneity and cardiac development, thus providing new clues for approaches to effective cardiac regeneration.

Keywords

mononuclear diploid cardiomyocytes / cell–cell communication / cardiac fibroblast / single-cell RNA sequencing / cardiac regeneration

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Acknowledgements

We would like to thank Prof. Bin Zhang and Prof. Nianguo Dong for their constructive suggestions, and all the laboratory members for critically reading the manuscript. This study was supported by the National Key Research and Development Program of China (No.2021YFA1101901) and the Fundamental Research Funds for the Central Universities, HUST (No. 2021GCRC073).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0987-9 and is accessible for authorized users.

Compliance with ethics guidelines

Miaomiao Zhu, Huamin Liang, Zhe Zhang, Hao Jiang, Jingwen Pu, Xiaoyi Hang, Qian Zhou, Jiacheng Xiang, and Ximiao He declare that they have no competing interests. All institutional and national guidelines for the care and use of laboratory animals were followed.

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