Characterization in mice of the resident mesenchymal niche maintaining AT2 stem cell proliferation in homeostasis and disease

Abstract

Resident mesenchymal cells (rMCs defined as Cd31^Neg Cd45^Neg Epcam^Neg ) control the proliferation and differentiation of alveolar epithelial type 2 (AT2) stem cells in vitro. The identity of these rMCs is still elusive. Among them, Axin2^Pos mesenchymal alveolar niche cells (MANCs), which are expressing Fgf7, have been previously described. We propose that an additional population of rMCs, expressing Fgf10 (called rMC-Sca1^Pos Fgf10^Pos ) are equally important to maintain AT2 stem cell proliferation. The alveolosphere model, based on the AT2-rMC co-culture in growth factor-reduced Matrigel, was used to test the efficiency of different rMC subpopulations isolated by FACS from adult murine lung to sustain the proliferation and differentiation of AT2 stem cells. We demonstrate that rMC-Sca1^Pos Fgf10^Pos cells are efficient to promote the proliferation and differentiation of AT2 stem cells. Co-staining of adult lung for Fgf10 mRNA and Sftpc protein respectively, indicate that 28% of Fgf10^Pos cells are located close to AT2 cells. Co-ISH for Fgf7 and Fgf10 indicate that these two populations do not significantly overlap. Gene arrays comparing rMC-Sca1^Pos Axin2^Pos and rMC-Sca1^Pos Fgf10^Pos support that these two cell subsets express differential markers. In addition, rMC function is decreased in obese ob/ob mutant compared to WT mice with a much stronger loss of function in males compared to females. In conclusion, rMC-Sca1^Pos Fgf10^Pos cells play important role in supporting AT2 stem cells proliferation and differentiation. This result sheds a new light on the subpopulations of rMCs contributing to the AT2 stem cell niche in homeostasis and in the context of pre-existing metabolic diseases.

Keywords: AT2; Fgf10; gender; obesity; resident mesenchymal niche.