Recapitulating human cardio-pulmonary co-development using simultaneous multilineage differentiation of pluripotent stem cells

  1. Wai Hoe Ng
  2. Elizabeth K Johnston
  3. Jun Jie Tan
  4. Jacqueline M Bliley
  5. Adam W Feinberg
  6. Donna B Stolz
  7. Ming Sun
  8. Piyumi Wijesekara
  9. Finn Hawkins
  10. Darrell N Kotton
  11. Xi Ren  Is a corresponding author
  1. Carnegie Mellon University, United States
  2. Universiti Sains Malaysia, Malaysia
  3. University of Pittsburgh, United States
  4. Boston University, United States

Abstract

The extensive crosstalk between the developing heart and lung is critical to their proper morphogenesis and maturation. However, there remains a lack of models that investigate the critical cardio-pulmonary mutual interaction during human embryogenesis. Here, we reported a novel stepwise strategy for directing the simultaneous induction of both mesoderm-derived cardiac and endoderm-derived lung epithelial lineages within a single differentiation of human induced pluripotent stem cells (hiPSCs) via temporal specific tuning of WNT and nodal signaling in the absence of exogenous growth factors. Using 3D suspension culture, we established concentric cardio-pulmonary micro-Tissues (mTs), and expedited alveolar maturation in the presence of cardiac accompaniment. Upon withdrawal of WNT agonist, the cardiac and pulmonary components within each dual-lineage mT effectively segregated from each other with concurrent initiation of cardiac contraction. We expect that our multilineage differentiation model will offer an experimentally tractable system for investigating human cardio-pulmonary interaction and tissue boundary formation during embryogenesis.

Data availability

All data supporting the findings of this study are available within the article and its supplementary files. Source data files have been provided for Figures 1 to 6.

Article and author information

Author details

  1. Wai Hoe Ng

    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, United States
    Competing interests
    Wai Hoe Ng, is a co-inventor of a related provisional patent application (No. 63/124422) entitled 'Methods for simultaneous cardio-pulmonary differentiation and alveolar maturation from human pluripotent stem cells'..
  2. Elizabeth K Johnston

    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, United States
    Competing interests
    Elizabeth K Johnston, is a co-inventor of a related provisional patent application (No. 63/124422) entitled 'Methods for simultaneous cardio-pulmonary differentiation and alveolar maturation from human pluripotent stem cells'..
  3. Jun Jie Tan

    Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
    Competing interests
    No competing interests declared.
  4. Jacqueline M Bliley

    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  5. Adam W Feinberg

    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  6. Donna B Stolz

    Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  7. Ming Sun

    Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  8. Piyumi Wijesekara

    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  9. Finn Hawkins

    Center for Regenerative Medicine, Boston University, Boston, United States
    Competing interests
    No competing interests declared.
  10. Darrell N Kotton

    Center for Regenerative Medicine, Boston University, Boston, MA, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9604-8476
  11. Xi Ren

    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, United States
    For correspondence
    xiren@cmu.edu
    Competing interests
    Xi Ren, is a co-inventor of a related provisional patent application (No. 63/124422) entitled 'Methods for simultaneous cardio-pulmonary differentiation and alveolar maturation from human pluripotent stem cells'..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3187-1311

Funding

Samuel & Emma Winters Foundation (A025662)

  • Xi Ren

Carnegie Mellon University

  • Xi Ren

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Paul W Noble, Cedars-Sinai Medical Centre, United States

Version history

  1. Received: February 25, 2021
  2. Preprint posted: March 3, 2021 (view preprint)
  3. Accepted: January 7, 2022
  4. Accepted Manuscript published: January 12, 2022 (version 1)
  5. Version of Record published: February 15, 2022 (version 2)

Copyright

© 2022, Ng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Wai Hoe Ng
  2. Elizabeth K Johnston
  3. Jun Jie Tan
  4. Jacqueline M Bliley
  5. Adam W Feinberg
  6. Donna B Stolz
  7. Ming Sun
  8. Piyumi Wijesekara
  9. Finn Hawkins
  10. Darrell N Kotton
  11. Xi Ren
(2022)
Recapitulating human cardio-pulmonary co-development using simultaneous multilineage differentiation of pluripotent stem cells
eLife 11:e67872.
https://doi.org/10.7554/eLife.67872

Share this article

https://doi.org/10.7554/eLife.67872

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