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

doi:10.1007/s11684-023-0987-9

Front. Med.

2023, Vol. 17

Issue (5) : 939-956 https://doi.org/10.1007/s11684-023-0987-9

RESEARCH ARTICLE

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

Miaomiao Zhu^1,^2,³, Huamin Liang^1,^2,³, Zhe Zhang¹, Hao Jiang^1,^2,³, Jingwen Pu^1,^2,³, Xiaoyi Hang^1,^2,³, Qian Zhou^1,^2,³, Jiacheng Xiang^1,^2,³, Ximiao He^1,^2,³(

)

¹. Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
². Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
³. Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan 430030, China

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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

Corresponding Author(s): Ximiao He

Just Accepted Date: 07 April 2023 Online First Date: 07 June 2023 Issue Date: 07 December 2023

Cite this article:

Miaomiao Zhu,Huamin Liang,Zhe Zhang, et al. Distinct mononuclear diploid cardiac subpopulation with minimal cell–cell communications persists in embryonic and adult mammalian heart[J]. Front. Med., 2023, 17(5): 939-956.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0987-9
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I5/939

Fig.1 Single-cell analysis of murine hearts during development from E17.5 to P8. (A) Uniform manifold approximation and projection (UMAP) clustering of 12 645 single cells isolated from E17.5, P2, and P8 murine hearts. Each dot represented a single cell. (B) Major cell types identified by the expression of established marker genes. CM, cardiomyocyte; EC, endothelial cell; FB, fibroblast; MP, macrophage; SMC, smooth muscle cell. (C) UMAP showing the expression distribution of selected markers for each cell type (Myh6 and Myl2 for CMs, Col1a1 and Dcn for FBs, Cdh5 and Pecam1 for ECs, Adgre1 and Csf1r for MPs, and Acta2 and Myh11 for SMCs). (D) Heat map displaying top five differentially expressed genes (DEGs) in each cell type. (E) Gene Ontology (GO) analysis of DEGs of CMs.

Fig.2 Transcriptional signatures of cardiomyocyte sub-clusters. (A) UMAP of CM clustering from E17.5, P2, and P8 murine hearts. Numbers and colors highlighted individual sub-clusters based on their transcriptomic phenotype. (B) UMAP colored by cell origin. (C) Heat map of top five markers for each CM sub-cluster in (A). (D) Functional enrichment in CM subpopulations. –log₁₀(P value) indicated the significance of enrichment, and dot size indicated the level of enrichment.

Fig.3 Pseudotemporal trajectory analyses revealing potential proliferative cardiomyocyte sub-clusters. (A–C) Monocle analysis showing the ordering of CMs along pseudotime trajectories. CMs were color-labeled by cell origin (A), sub-cluster (B), and pseudotime (C). (D) Violin plot of pseudotime for each sub-cluster. (E) Boxplot of single-cell entropy of each CM sub-cluster. (F) Single cell entropy and (G) lineage differentiation diagram predicted with Monocle and scEpath. (H) Cell-cycle distribution of each CM cluster.

Fig.4 Characterization of cardiomyocyte sub-clusters. (A) Gene scoring analysis using the molecular signatures of gene datasets for mitochondrion, glycolysis, calcium handling, and cardiomyocyte structure. See also the genes as indicated in Figs. S7A–S7D. (B) UMAP showing the expression of predicted silent mononuclear CM marker genes Myl4 and Tnni1. (C) Expression levels of Tnni1 and Myl4 in sub-clusters of CM4_(non-pMNDCM), CM6_(pMNDCM), and CM7_(interCM). (D) UMAP of CM clustering based on snRNA analysis of P2-11 hearts [42]. (E) Correlation heat map among CM4, CM6, and P2-11 CM clusters. (F) UMAP of all CMs derived from scRNA-seq CM0-CM7 and snRNA-seq P2-11 CM clusters. (G) Corresponding spatial distribution of clusters (left), CM4 (mid), and CM5 (right) by scoring the specific expression profiles. (H) Immunofluorescent staining of Tnni1 and Myl4 in single CMs isolated from P8 mouse hearts. Scale: 10 μm. n = 5.

Fig.5 Crosstalk in cardiac cell types. (A–C) Cell crosstalk network of all cell types in the heart for CM clusters within MP, EC, FB, and SMC (A); CM clusters between FB (B); and CM clusters between MP (C). Incoming (D) and outgoing (E) communication patterns of secreting cells. Dot size indicated the proportion of cell types in each communication pattern. (F–J) Inferred MK (F), PTN (G), CXCL (H), IL-16 (I), and TNF (J) signaling networks of all cell types in the heart.

Fig.6 Non-proliferative MNDCM existence in adult murine heart. (A) UMAP of CM clustering based on single-nucleus transcriptomics of W12 mouse hearts. (B) Correlation heat map between scRNA-seq CM0-CM7 and snRNA-seq W12 CM clusters. (C) UMAP of all CMs derived from scRNA-seq CM0-CM7 and snRNA-seq W12 CM clusters. (D) Gene scoring analysis using the molecular signatures of gene datasets for glycolysis, calcium handling, and cardiomyocyte structures. (E) Immunofluorescent staining of Tnni1 and Myl4 in heart slices from a P56 mouse. The atrium was evaluated as a positive control for Myl4⁺ atrial cells. Arrows indicated Tnnil⁺ (red), Myl4⁺ (green) and Myl4⁺Tnni1⁺ (pink) cells. n = 3. (F) Corresponding spatial distribution of CM4 and CM5 clusters by scoring the specific expression profiles in wild-type heart (sham) and 1, 7, and 14 days after myocardial infarction (MI) [41].

Fig.7 Schematic of CM cluster fate and intercellular crosstalk during development. Three cardiac developmental paths were proposed: two switching to CM maturation with close CM-fibroblast communications (left light blue panel and right light green panel) and the third maintaining MNDCM status with least CM-fibroblast communications (middle light pink panel). cp-likeCM (refer to CM0 in Fig. 3G, and as the same for the following): cardiac progenitor-like cardiomyocytes, interCM (CM1 and CM7): intermediate cardiomyocytes, mCM (CM2): mature cardiomyocytes, proMNDCM (CM3): mononuclear diploid cardiomyocyte (MNDCM) progenitor, non-pMNDCM (CM4): non-proliferative MNDCM, pMNDCM (CM6): proliferative MNDCM, EC-likeCM (CM5): endothelial like cardiomyocytes.

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