Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease
Dec 1, 2023ยท,,,,,,,,,,,,,,,,,,,ยท
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Anna B. Meier*
Dorota Zawada*
Maria Teresa De Angelis*
Laura D. Martens*
Gianluca Santamaria*
Sophie Zengerle
Monika Nowak-Imialek
Jessica Kornherr
Fangfang Zhang
Qinghai Tian
Cordula M. Wolf
Christian Kupatt
Makoto Sahara
Peter Lipp
Fabian J. Theis
Julien Gagneur
Alexander Goedel
Karl-Ludwig Laugwitz
Tatjana Dorn
Alessandra Moretti
Abstract
The 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.
Type
Publication
Nature Biotechnology