Tempo-spatial regulation of the Wnt pathway by FAM13A modulates the stemness of alveolar epithelial progenitors

Background: Family with Sequence Similarity 13, Member A (FAM13A) gene has been consistently associated with COPD by Genome-wide association studies (GWAS). Our previous study demonstrated that FAM13A was mainly expressed in the lung epithelial progenitors including Club cells and alveolar type II epithelial (ATII) cells. Fam13 alpha(-/-) mice were resistant to cigarette smoke (CS)-induced emphysema through promoting beta-catenin/Wnt activation. Given the important roles of beta-catenin/Wnt activation in alveolar regeneration during injury, it is unclear when and where FAM13A regulates the Wnt pathway, the requisite pathway for alveolar epithelial repair, in vivo during CS exposure in lung epithelial progenitors. Methods: Fam13 alpha(+/+) or Fam13 alpha(-/-) mice were crossed with TCF/Lef:H2B-GFP Wnt-signaling reporter mouse line to indicate beta-catenin/Wnt-activated cells labeled with GFP followed by acute (1 month) or chronic (7 months) CS exposure. Fluorescence-activated flow cytometry analysis, immunofluorescence and organoid culture system were performed to identify the beta-catenin/Wnt-activated cells in Fam13 alpha(+/+) or Fam13 alpha(-/-) mice exposed to CS. Fam13a;SftpcCreERT2;Rosa26RmTmG mouse line, where GFP labels ATII cells, was generated for alveolar organoid culture followed by analyses of organoid number, immunofluorescence and gene expression. Single cell RNA-seq data from COPD ever smokers and nonsmoker control lungs were further analyzed. Findings: We found that FAM13A-deficiency significantly increased Wnt activation mainly in lung epithelial cells. Consistently, after long-term CS exposure in vivo, FAM13A deficiency bestows alveolar epithelial progenitor cells with enhanced proliferation and differentiation in the ex vivo organoid model. Importantly, expression of FAM13A is significantly increased in human COPD-derived ATII cells compared to healthy ATII cells as suggested by single cell RNA-sequencing data. Interpretation: Our findings suggest that FAM13A-deficiency promotes the Wnt pathway-mediated ATII cell repair/regeneration, and thereby possibly mitigating CS-induced alveolar destruction. (C) 2021 The Author(s). Published by Elsevier B.V.

Automated summary

The study demonstrates that deficiency in FAM13A increases Wnt activation in lung epithelial cells, leading to enhanced proliferation and differentiation in alveolar epithelial progenitor cells after long-term CS exposure. Additionally, increased expression of FAM13A in human COPD-derived ATII cells compared to healthy ATII cells suggests a potential role in alveolar repair and regeneration.