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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.

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