First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany.
Regenerative Medicine in Cardiovascular Diseases, First Department of Medicine, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany.
Nat Biotechnol. 2023 Dec;41(12):1787-1800. doi: 10.1038/s41587-023-01718-7. Epub 2023 Apr 3.
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.
心外膜是脊椎动物心脏的间皮包膜，在胚胎发育过程中是多种心脏细胞谱系的来源，为心肌生长和修复提供了必不可少的信号。在这里，我们生成了自我组织的人类多能干细胞衍生的心外膜细胞，这些细胞表现出典型的左心室壁的心脏外膜和心肌的视黄酸依赖性形态、分子和功能模式。通过结合谱系追踪、单细胞转录组学和染色质可及性分析，我们描述了心外膜细胞的特化和分化过程，并在转录和形态水平上与人类胎儿发育进行了比较。然后，我们使用心外膜细胞来研究心脏细胞类型之间的功能串扰，从而深入了解 IGF2/IGF1R 和 NRP2 信号在人类心脏发生中的作用。最后，我们表明心外膜细胞模拟了先天性或应激诱导的肥大和纤维性重塑的多细胞发病机制。因此，心外膜细胞为心脏发育、疾病和再生中心外膜活性的测试提供了独特的平台。
