Title: Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells.
Authors: Jacob, Anjali; Morley, Michael; Hawkins, Finn; McCauley, Katherine B; Jean, J C; Heins, Hillary; Na, Cheng-Lun; Weaver, Timothy E; Vedaie, Marall; Hurley, Killian; Hinds, Anne; Russo, Scott J; Kook, Seunghyi; Zacharias, William; Ochs, Matthias; Traber, Katrina; Quinton, Lee J; Crane, Ana; Davis, Brian R; White, Frances V; Wambach, Jennifer; Whitsett, Jeffrey A; Cole, F Sessions; Morrisey, Edward E; Guttentag, Susan H; Beers, Michael F; Kotton, Darrell N
Published In Cell Stem Cell, (2017 10 05)
Abstract: 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.
PubMed ID: 28965766
MeSH Terms: Base Sequence; Cell Differentiation*; Cell Line; Cell Proliferation; Cell Self Renewal; Cell Separation; Epithelial Cells/cytology*; Epithelial Cells/ultrastructure; Gene Expression Profiling; Genes, Reporter; Humans; Lung Diseases/pathology; Models, Biological; Pluripotent Stem Cells/cytology*; Pulmonary Alveoli/cytology*; Pulmonary Alveoli/ultrastructure; Pulmonary Surfactants/metabolism; Thyroid Nuclear Factor 1/metabolism; Time Factors; Wnt Proteins/metabolism; Wnt Signaling Pathway