A35-31 Epithelial-derived MMP10 Is Required to Maintain Alveolar Type 2 Cell Stemness in Lung Fibrosis

Rationale

In both human and mouse tissues, matrix metalloproteinase 10 (MMP10) is expressed by macrophages and epithelial cells in response to tissue damage associated with injury, infection, or disease, including in IPF lungs. In lung infection and in skin and gut injury models, global deletion of MMP10 (Mmp10-/-) is associated with worse outcomes, and findings from these studies suggest that the overall protective effect of MMP10 is driven by macrophages. However, the role of epithelial MMP10 in response to lung injury remains unknown.

Methods

Mmp10 -/- and wildtype mice (8-12-weeks, both sexes) were intratracheally administered bleomycin (0.75 units/kg) once. Mice were tracked daily, and lungs were harvested at various times. At day 7, AT2 cells were FACS-sorted to establish 3D alveolospheres. The alveolospheres were imaged weekly to assess colony-forming efficiency (CFE) and size. The hydroxyproline assay was used to quantify lung fibrosis.

Results

Compared to wildtype mice, Mmp10-/- mice had significantly greater weight loss, inflammation, mortality, and fibrosis in the lungs. The bleomycin-injured AT2 cells from Mmp10-/- mice had lower colony-forming efficiency and smaller colony sizes than those from WT mice.

Conclusions

Our findings suggest that MMP10 is essential for AT2 cell stemness function in lung fibrosis. In addition to the protective macrophage-mediated functions of MMP10, our findings suggest that MMP10 also mediates protection through AT2 cells. We are exploring the involvement of MMP10 in AT2 differentiation and proliferation using histological assessment of lungs and alveolospheres. Further, we are studying the functional roles of MMP10 in AT2-specific MMP10 knockout mice that we have generated.

This abstract is funded by: NIH-NHLBI