Cell Stem Cell
Volume 20, Issue 6, 1 June 2017, Pages 844-857.e6
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Article
Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling

https://doi.org/10.1016/j.stem.2017.03.001Get rights and content
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Highlights

  • Wnt signaling regulates lung differentiation of human pluripotent stem cells

  • Withdrawal of Wnt signaling from lung progenitors prompts rapid proximal patterning

  • Purified lung progenitors differentiate to airway organoids in low Wnt conditions

  • Derived organoids exhibit CFTR-dependent swelling in response to forskolin

Summary

Effective derivation of functional airway organoids from induced pluripotent stem cells (iPSCs) would provide valuable models of lung disease and facilitate precision therapies for airway disorders such as cystic fibrosis. However, limited understanding of human airway patterning has made this goal challenging. Here, we show that cyclical modulation of the canonical Wnt signaling pathway enables rapid directed differentiation of human iPSCs via an NKX2-1+ progenitor intermediate into functional proximal airway organoids. We find that human NKX2-1+ progenitors have high levels of Wnt activation but respond intrinsically to decreases in Wnt signaling by rapidly patterning into proximal airway lineages at the expense of distal fates. Using this directed approach, we were able to generate cystic fibrosis patient-specific iPSC-derived airway organoids with a defect in forskolin-induced swelling that is rescued by gene editing to correct the disease mutation. Our approach has many potential applications in modeling and drug screening for airway diseases.

Keywords

directed differentiation
human pluripotent stem cells
lung development
Wnt signaling
cystic fibrosis
disease modeling
lung epithelium
airway epithelium

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