The COPD GWAS gene ADGRG6 instructs function and injury response in human iPSC-derived type II alveolar epithelial cells.

Autor:	Werder RB; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia., Berthiaume KA; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA., Merritt C; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Gallagher M; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA., Villacorta-Martin C; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA., Wang F; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA., Bawa P; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA., Malik V; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Lyons SM; Biochemistry Department, Boston University School of Medicine, Boston, MA 02118, USA., Basil MC; School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Morrisey EE; School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Kotton DN; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Zhou X; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Cho MH; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Wilson AA; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: awilson@bu.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2023 Oct 05; Vol. 110 (10), pp. 1735-1749. Date of Electronic Publication: 2023 Sep 20.
DOI:	10.1016/j.ajhg.2023.08.017
Abstrakt:	Emphysema and chronic obstructive pulmonary disease (COPD) most commonly result from the effects of environmental exposures in genetically susceptible individuals. Genome-wide association studies have implicated ADGRG6 in COPD and reduced lung function, and a limited number of studies have examined the role of ADGRG6 in cells representative of the airway. However, the ADGRG6 locus is also associated with DLCO/VA, an indicator of gas exchange efficiency and alveolar function. Here, we sought to evaluate the mechanistic contributions of ADGRG6 to homeostatic function and disease in type 2 alveolar epithelial cells. We applied an inducible CRISPR interference (CRISPRi) human induced pluripotent stem cell (iPSC) platform to explore ADGRG6 function in iPSC-derived AT2s (iAT2s). We demonstrate that ADGRG6 exerts pleiotropic effects on iAT2s including regulation of focal adhesions, cytoskeleton, tight junctions, and proliferation. Moreover, we find that ADGRG6 knockdown in cigarette smoke-exposed iAT2s alters cellular responses to injury, downregulating apical complexes in favor of proliferation. Our work functionally characterizes the COPD GWAS gene ADGRG6 in human alveolar epithelium. Competing Interests: Declaration of interests M.H.C. has received grant support from GSK and Bayer and speaking/consulting fees from Illumina, AstraZeneca, and Genentech. X.Z. has received grant support from Bayer. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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