Citation
Tan, Jun Jie and Guyette, Jacques P. and Miki, Kenji and Xiao, Ling and Kaur, Gurbani and Wu, Tong and Zhu, Liye and Hansen, Katrina J. and Ling, King Hwa and Milan, David J. and Ott, Harald C.
(2021)
Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro.
Nature Communications, 12.
art. no. 4997.
pp. 1-19.
ISSN 2041-1723
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.
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