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iPSC-derived Lung Organoids Aid the Search for Prenatal Lung Defect Treatments


Review of "Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Congenital diaphragmatic hernia (CDH), a condition associated with fetal lung compression and pulmonary hypoplasia at birth, is a common, costly, and severe congenital disability [1, 2] and, unfortunately, we currently lack a deep enough understanding of disease pathogenesis to manage this debilitating condition efficiently. The underlying causes of CDH remain unknown [3], and functional analyses of known associated gene variants remain challenging to study in animal models due to early embryonic lethality, a lack of conditional mutants, and the low/variable recapitulation of the CDH phenotype [4, 5].

In the hope of moving the field significantly forward, researchers led by Shaun M. Kunisaki (Johns Hopkins University School of Medicine, Baltimore, MD, USA) isolated cells from CDH fetuses and infants and developed induced pluripotent stem cell (iPSC)-derived three‐dimensional (3D) lung organoids that contain both pulmonary epithelial and mesenchymal cell types to model fetal lung development and determine the potential of cell‐based treatment strategies [6]. Overall, the findings described in this exciting new STEM CELLS Translational Medicine article support both primary cell‐intrinsic and secondary mechanical causes of altered development in the CDH lung.

After developing fully-pluripotent, genomically stable, and transgene-free CDH-iPSCs using non-integrating Sendai virus-mediated transduction of amniotic fluid or foreskin cells, the authors followed an established lung induction protocol [7] and formed multicellular lung organoids that possessed pulmonary epithelial structures, alveolar cell types, and mesenchymal derivatives, which corresponded to the pseudo glandular and early canalicular stages of lung development.

Notably, a detailed comparison of control lung organoids and CDH lung organoids highlighted significant differences, including the upregulation of extracellular matrix-related genes and differences in lung progenitor, type II alveolar epithelial cells, and myofibroblasts differentiation in the absence of mechanical compression forces in CDH lung organoids. To mirror the lung compression during in utero development, the authors evaluated control and CDH lung organoids following culture in an ex vivo mechanical compression apparatus [8] and discovered that compression prompted the significant downregulation of genes related to proximal and distal lung progenitor and the significant upregulation of genes associated with pro‐fibrotic mesenchymal fibroblasts in the CDH lung organoids only.

The authors note that subsequent studies will aim to elucidate additional disease‐relevant mechanical cues and explore the epithelial‐mesenchymal interactions that contribute to disease pathology during early lung development. Additionally, the further development of this lung organoid platform will allow the evaluation of pharmacologic agents such as pulmonary morphogens and growth factors to enhance perinatal lung development and differentiation.

For more on lung organoids and the ongoing development of treatments for CDH, stay tuned to the Stem Cells Portal!


  1. Putnam LR, Harting MT, Tsao K, et al., Congenital Diaphragmatic Hernia Defect Size and Infant Morbidity at Discharge. Pediatrics 2016;138:e20162043.
  2. Cameron DB, Graham DA, Milliren CE, et al., Quantifying the Burden of Interhospital Cost Variation in Pediatric Surgery: Implications for the Prioritization of Comparative Effectiveness Research. JAMA Pediatrics 2017;171:e163926-e163926.
  3. Rottier R and Tibboel D, Fetal Lung and Diaphragm Development in Congenital Diaphragmatic Hernia. Seminars in Perinatology 2005;29:86-93.
  4. Ackerman KG, Herron BJ, Vargas SO, et al., Fog2 Is Required for Normal Diaphragm and Lung Development in Mice and Humans. PLOS Genetics 2005;1:e10.
  5. Yu L, Wynn J, Cheung YH, et al., Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia. Human Genetics 2013;132:285-292.
  6. Kunisaki SM, Jiang G, Biancotti JC, et al., Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung. STEM CELLS Translational Medicine 2021;10:98-114.
  7. Dye BR, Hill DR, Ferguson MAH, et al., In vitro generation of human pluripotent stem cell derived lung organoids. eLife 2015;4:e05098.
  8. Tse JM, Cheng G, Tyrrell JA, et al., Mechanical compression drives cancer cells toward invasive phenotype. Proceedings of the National Academy of Sciences 2012;109:911.