Open AccessHuman induced pluripotent stem cell‐derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung
Author(s) -
Kunisaki Shaun M.,
Jiang Guihua,
Biancotti Juan C.,
Ho Kenneth K. Y.,
Dye Briana R.,
Liu Allen P.,
Spence Jason R.
Publication year - 2021
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.20-0199
Subject(s) - congenital diaphragmatic hernia , induced pluripotent stem cell , ex vivo , stem cell , progenitor cell , pathology , lung , embryonic stem cell , mesenchymal stem cell , pulmonary hypoplasia , biology , medicine , fetus , microbiology and biotechnology , in vivo , genetics , pregnancy , gene
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.