GSE172059
Hedgehog-Responsive PDGFRa(+) Fibroblasts are Necessary for Maintenance of a Unique Pool of Alveolar Epithelial Progenitor Cells During Alveologenesis
The adult lung alveolus is a flexible 3D structure composed of multiple epithelial, endothelial, and mesenchymal cell types. Two highly specialized alveolar type I (AT1) and type II (AT2) cells, derived from epithelial progenitors, form the inner lining of the alveolus. During alveologenesis, the increasing demand for epithelial cells to cover the surface of the expansive number of alveoli is met by proliferating progenitor cells. There is presently little information about the identity of this population, and the niche microenvironment that controls its proliferation. We show that during alveologenesis genetic inactivation of TGF??receptors in hedgehog-responsive, PDGFRa(+) mesodermal cells previously identified as secondary crest myofibroblasts or SCMF reduces their number, and depletes a unique pool of proliferative epithelial progenitors, without significantly impacting differentiation of cells existing the pool. SCMF are a source of both extracellular matrix and secreted trophic molecules and may thus constitute a key component of the epithelial progenitor niche during alveologenesis. Paralleling the mouse model, we found evidence of reduced proliferation of SFTPC(+) progenitors in lungs of human preterm infants who died with bronchopulmonary dysplasia or BPD.  SCMF are a transient cell population, which are depleted at completion of alveologenesis, making them a unique stage-dependent niche mesodermal cell type in mammalian organs. Overall design: scRNAseq of PN14 lungs from wild type (Ctrl) and Tgfbr1&2-/- mice (Mut).