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A multimodal iPSC platform for cystic fibrosis drug testing

Author

Listed:
  • Andrew Berical

    (Center for Regenerative Medicine of Boston University and Boston Medical Center
    Boston University and Boston Medical Center)

  • Rhianna E. Lee

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Junjie Lu

    (Cystic Fibrosis Foundation)

  • Mary Lou Beermann

    (Center for Regenerative Medicine of Boston University and Boston Medical Center)

  • Jake A. Le Suer

    (Center for Regenerative Medicine of Boston University and Boston Medical Center)

  • Aditya Mithal

    (Center for Regenerative Medicine of Boston University and Boston Medical Center)

  • Dylan Thomas

    (Center for Regenerative Medicine of Boston University and Boston Medical Center)

  • Nicole Ranallo

    (Center for Regenerative Medicine of Boston University and Boston Medical Center)

  • Megan Peasley

    (Cystic Fibrosis Foundation)

  • Alex Stuffer

    (Cystic Fibrosis Foundation)

  • Katherine Bukis

    (Cystic Fibrosis Foundation)

  • Rebecca Seymour

    (Cystic Fibrosis Foundation)

  • Jan Harrington

    (Cystic Fibrosis Foundation)

  • Kevin Coote

    (Cystic Fibrosis Foundation)

  • Hillary Valley

    (Cystic Fibrosis Foundation)

  • Killian Hurley

    (Education and Research Centre, Beaumont Hospital
    Royal College of Surgeons in Ireland)

  • Paul McNally

    (RCSI University of Medicine and Health Sciences
    Children’s Health Ireland)

  • Gustavo Mostoslavsky

    (Center for Regenerative Medicine of Boston University and Boston Medical Center)

  • John Mahoney

    (Cystic Fibrosis Foundation)

  • Scott H. Randell

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Finn J. Hawkins

    (Center for Regenerative Medicine of Boston University and Boston Medical Center
    Boston University and Boston Medical Center)

Abstract

Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.

Suggested Citation

  • Andrew Berical & Rhianna E. Lee & Junjie Lu & Mary Lou Beermann & Jake A. Le Suer & Aditya Mithal & Dylan Thomas & Nicole Ranallo & Megan Peasley & Alex Stuffer & Katherine Bukis & Rebecca Seymour & J, 2022. "A multimodal iPSC platform for cystic fibrosis drug testing," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31854-8
    DOI: 10.1038/s41467-022-31854-8
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    References listed on IDEAS

    as
    1. Daniel T. Montoro & Adam L. Haber & Moshe Biton & Vladimir Vinarsky & Brian Lin & Susan E. Birket & Feng Yuan & Sijia Chen & Hui Min Leung & Jorge Villoria & Noga Rogel & Grace Burgin & Alexander M. T, 2018. "A revised airway epithelial hierarchy includes CFTR-expressing ionocytes," Nature, Nature, vol. 560(7718), pages 319-324, August.
    2. Aditya Mithal & Amalia Capilla & Dar Heinze & Andrew Berical & Carlos Villacorta-Martin & Marall Vedaie & Anjali Jacob & Kristine Abo & Aleksander Szymaniak & Megan Peasley & Alexander Stuffer & John , 2020. "Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Lindsey W. Plasschaert & Rapolas Žilionis & Rayman Choo-Wing & Virginia Savova & Judith Knehr & Guglielmo Roma & Allon M. Klein & Aron B. Jaffe, 2018. "A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte," Nature, Nature, vol. 560(7718), pages 377-381, August.
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