Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro

Jun Jie Tan (), Jacques P. Guyette, Kenji Miki, Ling Xiao, Gurbani Kaur, Tong Wu, Liye Zhu, Katrina J. Hansen, King-Hwa Ling, David J. Milan and Harald C. Ott ()
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Jun Jie Tan: Massachusetts General Hospital
Jacques P. Guyette: Massachusetts General Hospital
Kenji Miki: Massachusetts General Hospital
Ling Xiao: Harvard Medical School
Gurbani Kaur: Massachusetts General Hospital
Tong Wu: Massachusetts General Hospital
Liye Zhu: Massachusetts General Hospital
Katrina J. Hansen: Worcester Polytechnic Institute, Dept. of Biomedical Engineering
King-Hwa Ling: Harvard Medical School
David J. Milan: Harvard Medical School
Harald C. Ott: Massachusetts General Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24921-z

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