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- Title
Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro.
- Authors
Tan, Jun Jie; Guyette, Jacques P.; Miki, Kenji; Xiao, Ling; Kaur, Gurbani; Wu, Tong; Zhu, Liye; Hansen, Katrina J.; Ling, King-Hwa; Milan, David J.; Ott, Harald C.
- Abstract
Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro. The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.
- Subjects
SMOOTH muscle; MESODERM; HEART cells; ORGANIZATION; MORPHOGENESIS
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-24921-z