Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung.

Autor: Kunisaki SM; Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.; Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA., Jiang G; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA., Biancotti JC; Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.; Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA., Ho KKY; Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA., Dye BR; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA., Liu AP; Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA., Spence JR; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Jazyk: angličtina
Zdroj: Stem cells translational medicine [Stem Cells Transl Med] 2021 Jan; Vol. 10 (1), pp. 98-114. Date of Electronic Publication: 2020 Sep 19.
DOI: 10.1002/sctm.20-0199
Abstrakt: Three-dimensional lung organoids (LOs) derived from pluripotent stem cells have the potential to enhance our understanding of disease mechanisms and to enable novel therapeutic approaches in neonates with pulmonary disorders. We established a reproducible ex vivo model of lung development using transgene-free human induced pluripotent stem cells generated from fetuses and infants with Bochdalek congenital diaphragmatic hernia (CDH), a polygenic disorder associated with fetal lung compression and pulmonary hypoplasia at birth. Molecular and cellular comparisons of CDH LOs revealed impaired generation of NKX2.1 + progenitors, type II alveolar epithelial cells, and PDGFRα + myofibroblasts. We then subjected these LOs to disease relevant mechanical cues through ex vivo compression and observed significant changes in genes associated with pulmonary progenitors, alveolar epithelial cells, and mesenchymal fibroblasts. Collectively, these data suggest both primary cell-intrinsic and secondary mechanical causes of CDH lung hypoplasia and support the use of this stem cell-based approach for disease modeling in CDH.
(© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)
Databáze: MEDLINE
Externí odkaz: