Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells

Anjali Jacob, Michael Morley, Finn Hawkins, Katherine B. McCauley, J. C. Jean, Hillary Heins, Cheng Lun Na, Timothy E. Weaver, Marall Vedaie, Killian Hurley, Anne Hinds, Scott J. Russo, Seunghyi Kook, William Zacharias, Matthias Ochs, Katrina Traber, Lee J. Quinton, Ana Crane, Brian R. Davis, Frances V. WhiteJennifer Wambach, Jeffrey A. Whitsett, F. Sessions Cole, Edward E. Morrisey, Susan H. Guttentag, Michael F. Beers, Darrell N. Kotton

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


Lung alveoli, which are unique to air-breathing organisms, have been challenging to generate from pluripotent stem cells (PSCs) in part because there are limited model systems available to provide the necessary developmental roadmaps for in vitro differentiation. Here we report the generation of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, from human PSCs. Using multicolored fluorescent reporter lines, we track and purify human SFTPC+ alveolar progenitors as they emerge from endodermal precursors in response to stimulation of Wnt and FGF signaling. Purified PSC-derived SFTPC+ cells form monolayered epithelial “alveolospheres” in 3D cultures without the need for mesenchymal support, exhibit self-renewal capacity, and display additional AEC2 functional capacities. Footprint-free CRISPR-based gene correction of PSCs derived from patients carrying a homozygous surfactant mutation (SFTPB121ins2) restores surfactant processing in AEC2s. Thus, PSC-derived AEC2s provide a platform for disease modeling and future functional regeneration of the distal lung. Jacob et al. differentiate human pluripotent stem cells (PSCs) into type II alveolar cells (iAEC2s). They find that iAEC2s display many of the functions, transcriptomic features, and surfactant-processing capacities that characterize primary cells. Finally, they derive AEC2s from gene-edited, patient-specific PSCs to model surfactant protein B deficiency in vitro.

Original languageEnglish
Pages (from-to)472-488.e10
JournalCell Stem Cell
Issue number4
StatePublished - Oct 5 2017


  • alveolar epithelial cell
  • development
  • disease modeling
  • embryonic stem cells
  • gene editing
  • human induced pluripotent stem cells
  • lung
  • surfactant
  • surfactant protein B

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