Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease

Author:

Meier Anna B.ORCID,Zawada DorotaORCID,De Angelis Maria Teresa,Martens Laura D.ORCID,Santamaria GianlucaORCID,Zengerle Sophie,Nowak-Imialek Monika,Kornherr Jessica,Zhang Fangfang,Tian Qinghai,Wolf Cordula M.,Kupatt ChristianORCID,Sahara MakotoORCID,Lipp Peter,Theis Fabian J.,Gagneur JulienORCID,Goedel Alexander,Laugwitz Karl-LudwigORCID,Dorn Tatjana,Moretti AlessandraORCID

Abstract

AbstractThe epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that are essential to myocardial growth and repair. Here we generate self-organizing human pluripotent stem cell-derived epicardioids that display retinoic acid-dependent morphological, molecular and functional patterning of the epicardium and myocardium typical of the left ventricular wall. By combining lineage tracing, single-cell transcriptomics and chromatin accessibility profiling, we describe the specification and differentiation process of different cell lineages in epicardioids and draw comparisons to human fetal development at the transcriptional and morphological levels. We then use epicardioids to investigate the functional cross-talk between cardiac cell types, gaining new insights into the role of IGF2/IGF1R and NRP2 signaling in human cardiogenesis. Finally, we show that epicardioids mimic the multicellular pathogenesis of congenital or stress-induced hypertrophy and fibrotic remodeling. As such, epicardioids offer a unique testing ground of epicardial activity in heart development, disease and regeneration.

Funder

Fondazione Umberto Veronesi

Deutsche Herzstiftung e.V. Gerd-Killian Award

Deutsche Forschungsgemeinschaft

Deutsches Zentrum für Herz-Kreislaufforschung

Publisher

Springer Science and Business Media LLC

Subject

Biomedical Engineering,Molecular Medicine,Applied Microbiology and Biotechnology,Bioengineering,Biotechnology

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