02368nas a2200409   4500000000100000000000100001008004100002260001500043653003500058653002700093653002600120100001800146700001800164700002800182700002100210700002400231700002000255700002500275700002100300700001900321700001700340700002000357700002100377700001800398700001500416700002000431700001900451700002100470700002500491700001700516700002300533245011800556856005500674300000900729520120600738022001401944       2023                            d  c2023-04-0310ainduced pluripotent stem cells10aPluripotent Stem Cells10aRegenerative Medicine1 aAnna B. Meier1 aDorota Zawada1 aMaria Teresa De Angelis1 aLaura D. Martens1 aGianluca Santamaria1 aSophie Zengerle1 aMonika Nowak-Imialek1 aJessica Kornherr1 aFangfang Zhang1 aQinghai Tian1 aCordula M. Wolf1 aChristian Kupatt1 aMakoto Sahara1 aPeter Lipp1 aFabian J. Theis1 aJulien Gagneur1 aAlexander Goedel1 aKarl-Ludwig Laugwitz1 aTatjana Dorn1 aAlessandra Moretti00aEpicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease  uhttps://www.nature.com/articles/s41587-023-01718-7  a1-143 aThe 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.  a1546-1696