A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity
Vincent R. Knight-Schrijver, Hongorzul Davaapil, Semih Bayraktar, Alexander D. B. Ross, Kazumasa Kanemaru, James Cranley, Monika Dabrowska, Minal Patel, Krzysztof Polanski, Xiaoling He, Ludovic Vallier, Sarah Teichmann, Laure Gambardella, Sanjay Sinha
Abstract
Re-activating quiescent adult epicardium represents a potential therapeutic approach for human cardiac regeneration. However, the exact molecular differences between inactive adult and active fetal epicardium are not known. In this study, we combined fetal and adult human hearts using single-cell and single-nuclei RNA sequencing and compared epicardial cells from both stages. We found that a migratory fibroblast-like epicardial population only in the fetal heart and fetal epicardium expressed angiogenic gene programs, whereas the adult epicardium was solely mesothelial and immune responsive. Furthermore, we predicted that adult hearts may still receive fetal epicardial paracrine communication, including WNT signaling with endocardium, reinforcing the validity of regenerative strategies that administer or reactivate epicardial cells in situ. Finally, we explained graft efficacy of our human embryonic stem-cell-derived epicardium model by noting its similarity to human fetal epicardium. Overall, our study defines epicardial programs of regenerative angiogenesis absent in adult hearts, contextualizes animal studies and defines epicardial states required for effective human heart regeneration.
Datasets
1. Integrated adult and foetal hearts
Metadata
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clusters.high.res
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HCAHeart78808621066 cells D2_Sanger-Nuclei5045 cells D4_Sanger-Nuclei3748 cells D3_Sanger-Nuclei3420 cells D7_Sanger-Nuclei3382 cells D6_Sanger-Nuclei3378 cells D5_Sanger-Nuclei2825 cells D6_Sanger-Cells2121 cells D5_Sanger-Cells1865 cells D3_Sanger-Cells1561 cells D7_Sanger-Cells1475 cells Endothelial_cells11487 cells SMCs_&_Pericytes7916 cells Epicardial_cells1912 cells B_cells_Mast_cells1126 cells Myeloid_Immune_Cells8228 cells Endothelial_Capillaries5064 cells Smooth_Muscle_Cells4406 cells Lymphoid_Immune_Cells3715 cells Endothelial_Other1567 cells Endothelial_Arterial1537 cells Epicardium_Meso1495 cells Immature_Cardiomyocytes1391 cells Endothelial_Venous896 cells Epicardium_FB-like317 cells Pericytes_Stromal170 cells Epicardium_Proliferating100 cells Endothelial_Capillaries5064 cells Smooth_Muscle_Cells4406 cells Immature_Cardiomyocytes4014 cells Ventricular_Cardiomyocytes3086 cells Atrial_Cardiomyocytes2563 cells Fibroblast-like2351 cells Immature_FB-like2122 cells Immature_Endothelium1718 cells Endothelial_Other1567 cells Endothelial_Arterial1537 cells NeuronalCells_Mature1523 cells Epicardium_Meso1495 cells Myeloid_Proliferating1437 cells NeuronalCells_Dendritic1204 cells Immature_Neuralcrest1154 cells Endothelial_Venous896 cells Epicardium_FB-like317 cells Pericytes_Stromal170 cells Immature_Neuronal168 cells NeuronalCells_Immature123 cells Epicardium_Proliferating100 cells adult_Cardiomyocytes5706 cells foetal_Immature_other4964 cells adult_Myeloid_Immune_Cells4905 cells adult_Fibroblasts4630 cells foetal_Fibroblasts4207 cells adult_Endothelial_Capillaries3497 cells foetal_Myeloid_Immune_Cells3323 cells foetal_Smooth_Muscle_Cells3020 cells foetal_Cardiomyocytes2566 cells adult_Pericytes2222 cells adult_Lymphoid_Immune_Cells2059 cells foetal_Neuronal_Cells2014 cells foetal_Endocardial1667 cells foetal_Lymphoid_Immune_Cells1656 cells foetal_Endothelial_Capillaries1567 cells adult_Smooth_Muscle_Cells1386 cells foetal_Immature_Cardiomyocytes1310 cells foetal_Pericytes1118 cells foetal_Endothelial_Other1104 cells foetal_Endothelial_Arterial903 cells adult_Neuronal_Cells836 cells foetal_Epicardium_Meso790 cells adult_Endocardial756 cells adult_Epicardium_Meso705 cells adult_Adipocytes700 cells adult_Endothelial_Venous648 cells adult_Endothelial_Arterial634 cells adult_Endothelial_Other463 cells adult_Immature_other395 cells foetal_Epicardium_FB-like315 cells foetal_Endothelial_Venous248 cells adult_Pericytes_Stromal154 cells foetal_Epicardium_Proliferating100 cells adult_Immature_Cardiomyocytes81 cells foetal_Pericytes_Stromal16 cells adult_Epicardium_FB-like2 cells NCBITaxon:960660668 cells UBERON:003521318775 cells UBERON:000209817010 cells HsapDv:000004715235 cells HsapDv:000024115046 cells HsapDv:000024010026 cells cardiac muscle cell8272 cells capillary endothelial cell5064 cells smooth muscle cell4406 cells innate lymphoid cell3715 cells endocardial cell2423 cells mesothelial cell of epicardium1595 cells endothelial cell1567 cells endothelial cell of artery1537 cells fetal cardiomyocyte1391 cells vein endothelial cell896 cells cardiac mesenchymal cell317 cells basal zone of heart18775 cells left cardiac atrium7215 cells right cardiac atrium5608 cells heart right ventricle4522 cells heart left ventricle4348 cells interventricular septum3190 cells 10th week post-fertilization human stage15235 cells seventh decade human stage15046 cells sixth decade human stage10026 cells 12th week post-fertilization human stage8332 cells 9th week post-fertilization human stage7322 cells eighth decade human stage4707 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/43b45a20-a969-49ac-a8e8-8c84b211bd01
Alias names
GSE216019, Integrated adult and foetal heart single-cell RNA sequencing, PMID36938497, PMC7614330
Cite this study
Knight-Schrijver, V.R., Davaapil, H., Bayraktar, S., Ross, A.D., Kanemaru, K., Cranley, J., Dabrowska, M., Patel, M., Polanski, K., He, X. and Vallier, L., 2022. A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity. Nature cardiovascular research, 1(12), pp.1215-1229. https://doi.org/10.1038/s44161-022-00183-w
