Deletion of the PDGFR-β gene affects key fibroblast functions important for wound healing

This study provides new perspectives of the unique aspects of platelet-derived growth factor β-receptor (PDGFR-β) signaling and biological responses through the establishment of a mutant mouse strain in which two loxP sequences were inserted into the introns of PDGFR-β genome sequences. Isolation of skin fibroblasts from the mutant mice and Cre recombinase transfection in vitro induced PDGFR-β gene deletion (PDGFR-β^Δ/Δ). The resultant depletion of the PDGFR-β protein significantly attenuated platelet-derived growth factor (PDGF)-BB-induced cell migration, proliferation, and protection from H ₂O₂-induced apoptosis of the cultured PDGFR- β^Δ/Δ dermal fibroblasts. PDGF-AA and fetal bovine serum were mitogenic and antiapoptotic but were unable to induce the migration in PDGFR-β^Δ/Δ fibroblasts. Concerning the PDGF signaling, PDGF-BB-induced phosphorylation of Akt, ERK1/2, and JNK, but not p38, decreased in PDGFR-β^Δ/Δ fibroblasts, but PDGF-AA-induced signaling was not altered. Overexpression of the phospholipid phosphatases, SHIP2 and/or PTEN, inhibited PDGF-BB-induced phosphorylation of Akt and ERK1/2 in PDGFR-β^Δ/Δ fibroblasts but did not affect that of JNK and p38. These results indicate that disruption of distinct PDGFR-β signaling pathways in PDGFR-β^Δ/Δ dermal fibroblasts impaired their proliferation and survival, but completely inhibits migratory response, and that PDGF-BB-induced phosphorylation of Akt and ERK ^1/2 possibly mediated by PDGFR-α is regulated, at least in part, by the lipid phosphatases SHIP2 and/or PTEN. Thus, the PDGFR-β function on dermal fibroblasts appears to be critical in PDGF-BB action for skin wound healing and is clearly distinctive from that of PDGFR-α in the ligand-induced biological responses and the underlying properties of cellular signaling.