Stem Cells Transl Med

. 2020 Sep 19. doi: 10.1002/sctm.20-0199. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32949227/

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

Shaun M Kunisaki ^1 2, Guihua Jiang ³, Juan C Biancotti ^1 2, Kenneth K Y Ho ⁴, Briana R Dye ⁵, Allen P Liu ⁴, Jason R Spence ^5 6Affiliations expand

• PMID: 32949227
• DOI: 10.1002/sctm.20-0199

Free article

Abstract

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.

Keywords: congenital diaphragmatic hernia; fetal lung; induced pluripotent stem cells; lung organoids; mechanical compression.

© 2020 The Authors. STEM CELLS Translational Medicine published by Wiley Periodicals LLC on behalf of AlphaMed Press.