Regulation of fibroblast lipid storage and myofibroblast phenotypes during alveolar septation in mice

摘要

Signaling through platelet-derived growth factor receptor-a (PDGFRa) is required for alveolar septation and participates in alveolar regeneration after pneumonectomy. In both adipose tissue and skeletal muscle, bipotent pdgfra-expressing progenitors expressing delta-like ligand-1 or sex-determining region Y box 9 (Sox9) may differentiate into either lipid storage cells or myofibroblasts. We analyzed markers of mesen-chymal progenitors and differentiation in lung fibroblasts (LF) with different levels (absent, low, or high) of pdgfra gene expression. A larger proportion of p^g/ra-expressing than nonexpressing LF contained Sox9. Neutral lipids, CD166, and Tcf21 were more abundant in LF with a lower compared with a higher level of pdgfra gene expression. PDGF-A increased Sox9 in primary LF cultures, suggesting that active signaling through PDGFRa is required to maintain Sox9. As alveolar septation progresses from postnatal day (P) 8 to P12, fewer pdgfra-expvessing LF contain Sox9, whereas more of these LF contain myocardin-like transcription factor-A, showing that Sox9 diminishes as LF become myofibroblasts. At P8, neutral lipid droplets predominate in LF with the lower level of pdgfra gene expression, whereas transgelin (tagln) was predominantly expressed in LF with higher pdgfra gene expression. Targeted deletion of pdgfra in LF, which expressed tagln, reduced Sox9 in a-actin (a-SMA, ACTA2)-containing LF, whereas it increased the abundance of cell surface delta-like protein-1 (as well as peroxisome proliferator-activated receptor-7 and tcfll mRNA in LF, which also expressed stem cell antigen-1). Thus pdgfra deletion differentially alters delta-like protein-1 and Sox9, suggesting that targeting different downstream pathways in PDGF-A-responsive LF could identify strategies that promote lung regeneration without initiating fibrosis.