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Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice
Harold A. Chapman, … , Ying Wei, Thiennu H. Vu
Harold A. Chapman, … , Ying Wei, Thiennu H. Vu
Published June 23, 2011
Citation Information: J Clin Invest. 2011;121(7):2855-2862. https://doi.org/10.1172/JCI57673.
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Research Article

Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice

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Abstract

Laminins and their integrin receptors are implicated in epithelial cell differentiation and progenitor cell maintenance. We report here that a previously unrecognized subpopulation of mouse alveolar epithelial cells (AECs) expressing the laminin receptor α6β4, but little or no pro–surfactant C (pro-SPC), is endowed with regenerative potential. Ex vivo, this subpopulation expanded clonally as progenitors but also differentiated toward mature cell types. Integrin β4 itself was not required for AEC proliferation or differentiation. An in vivo embryonic lung organoid assay, which we believe to be novel, was used to show that purified β4+ adult AECs admixed with E14.5 lung single-cell suspensions and implanted under kidney capsules self-organized into distinct Clara cell 10-kDa secretory protein (CC10+) airway-like and SPC+ saccular structures within 6 days. Using a bleomycin model of lung injury and an SPC-driven inducible cre to fate-map AECs, we found the majority of type II AECs in fibrotic areas were not derived from preexisting type II AECs, demonstrating that SPC– progenitor cells replenished type II AECs during repair. Our findings support the idea that there is a stable AEC progenitor population in the adult lung, provide in vivo evidence of AEC progenitor cell differentiation after parenchymal injury, and identify a strong candidate progenitor cell for maintenance of type II AECs during lung repair.

Authors

Harold A. Chapman, Xiaopeng Li, Jonathan P. Alexander, Alexis Brumwell, Walter Lorizio, Kevin Tan, Arnoud Sonnenberg, Ying Wei, Thiennu H. Vu

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Figure 1

Identification and location of β4+ AECs in murine lungs.

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Identification and location of β4+ AECs in murine lungs.
   
(A) FACS pl...
(A) FACS plot of α6 and β4 on AECs from WT and Fβ4SC mice. Residual β4 staining in the Fβ4SC mice is nonspecific secondary antibody. Percentages denote the fraction of cells within the boxed regions. (B) Differential cell counts of β4+ and β4– cells purified by flow cytometry from normal lungs (mean ± SD, n = 6). (C) β4 immunostaining in WT lungs showing diffusely stained cells near the bronchoalveolar junction along with CC10 staining and the merged images. Note that not all CC10+ cells were β4+. Basilar staining of airway β4 was apparent near the airway end of the junctional region. There was a lack of costaining of SPC with β4+ cells in the alveolar region (see also Supplemental Figure 3). Scale bar: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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