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

Author

Listed:
  • Jun Jie Tan

    (Massachusetts General Hospital
    Harvard Medical School
    Universiti Sains Malaysia)

  • Jacques P. Guyette

    (Massachusetts General Hospital
    Harvard Medical School)

  • Kenji Miki

    (Massachusetts General Hospital
    Harvard Medical School
    Kyoto University)

  • Ling Xiao

    (Harvard Medical School
    Massachusetts General Hospital)

  • Gurbani Kaur

    (Massachusetts General Hospital)

  • Tong Wu

    (Massachusetts General Hospital
    Harvard Medical School)

  • Liye Zhu

    (Massachusetts General Hospital
    Harvard Medical School)

  • Katrina J. Hansen

    (Worcester Polytechnic Institute, Dept. of Biomedical Engineering)

  • King-Hwa Ling

    (Harvard Medical School
    Universiti Putra Malaysia)

  • David J. Milan

    (Harvard Medical School
    Massachusetts General Hospital
    Leducq Foundation)

  • Harald C. Ott

    (Massachusetts General Hospital
    Harvard Medical School
    Massachusetts General Hospital
    Harvard Stem Cell Institute)

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.

Suggested Citation

  • 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 & Harald C. Ott, 2021. "Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24921-z
    DOI: 10.1038/s41467-021-24921-z
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    Cited by:

    1. Mariana A. Branco & Tiago P. Dias & Joaquim M. S. Cabral & Perpetua Pinto-do-Ó & Maria Margarida Diogo, 2022. "Human multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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