Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells

Finn J Hawkins; Shingo Suzuki; Mary Lou Beermann; Cristina Barillà; Ruobing Wang; Carlos Villacorta-Martin; Andrew Berical; J C Jean; Jake Le Suer; Taylor Matte; Chantelle Simone-Roach; Yang Tang; Thorsten M Schlaeger; Ana M Crane; Nadine Matthias; Sarah X L Huang; Scott H Randell; Joshua Wu; Jason R Spence; Gianni Carraro; Barry R Stripp; Andras Rab; Eric J Sorsher; Amjad Horani; Steven L Brody; Brian R Davis; Darrell N Kotton

doi:10.1016/j.stem.2020.09.017

Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells

Cell Stem Cell. 2021 Jan 7;28(1):79-95.e8. doi: 10.1016/j.stem.2020.09.017. Epub 2020 Oct 23.

Authors

Finn J Hawkins¹, Shingo Suzuki², Mary Lou Beermann³, Cristina Barillà², Ruobing Wang⁴, Carlos Villacorta-Martin³, Andrew Berical¹, J C Jean³, Jake Le Suer¹, Taylor Matte³, Chantelle Simone-Roach⁴, Yang Tang⁵, Thorsten M Schlaeger⁶, Ana M Crane², Nadine Matthias², Sarah X L Huang², Scott H Randell⁷, Joshua Wu⁸, Jason R Spence⁹, Gianni Carraro¹⁰, Barry R Stripp¹⁰, Andras Rab¹¹, Eric J Sorsher¹¹, Amjad Horani¹², Steven L Brody¹², Brian R Davis¹³, Darrell N Kotton¹⁴

Affiliations

¹ Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA.
² Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.
³ Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA.
⁴ Pulmonary and Respiratory Diseases, Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Boston Children's Hospital Stem Cell Program, Boston, MA 02115, USA.
⁶ Boston Children's Hospital Stem Cell Program, Boston, MA 02115, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
⁷ Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁹ Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109, USA.
¹⁰ Department of Medicine, Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹¹ Emory University School of Medicine, Atlanta, GA 30322, USA.
¹² Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹³ Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: brian.r.davis@uth.tmc.edu.
¹⁴ Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA. Electronic address: dkotton@bu.edu.

Abstract

The derivation of tissue-specific stem cells from human induced pluripotent stem cells (iPSCs) would have broad reaching implications for regenerative medicine. Here, we report the directed differentiation of human iPSCs into airway basal cells ("iBCs"), a population resembling the stem cell of the airway epithelium. Using a dual fluorescent reporter system (NKX2-1^GFP;TP63^tdTomato), we track and purify these cells as they first emerge as developmentally immature NKX2-1^GFP+ lung progenitors and subsequently augment a TP63 program during proximal airway epithelial patterning. In response to primary basal cell medium, NKX2-1^GFP+/TP63^tdTomato+ cells display the molecular and functional phenotype of airway basal cells, including the capacity to self-renew or undergo multi-lineage differentiation in vitro and in tracheal xenografts in vivo. iBCs and their differentiated progeny model perturbations that characterize acquired and genetic airway diseases, including the mucus metaplasia of asthma, chloride channel dysfunction of cystic fibrosis, and ciliary defects of primary ciliary dyskinesia.

Keywords: airway regeneration; basal cells; directed differentiation; induced pluripotent stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Epithelial Cells
Humans
Induced Pluripotent Stem Cells*
Lung
Pluripotent Stem Cells*
Trachea

Abstract

Publication types

MeSH terms

Grants and funding