Molecular characterization of suburothelial fibrosis in murine acute recurrent bladder inflammation

초록

Chronic fibrosis replaces functional organ tissue with scar tissue by overproduction of a thick and stiff extracellular matrix. Bladder fibrosis decreases bladder compliance, ultimately resulting in overactive bladder. The phenoconversion of fibroblasts into myofibroblasts is the defining feature of fibrosis. Recently, regionally distinct populations of bladder platelet-derived growth factor receptor alpha positive (PDGFR alpha+) cells were identified as fibroblasts. Because of this heterogeneity, the identity of the bladder fibroblast cells that undergo phenotypic conversion into myofibroblasts is not clear. The current study utilized cyclophosphamide (CYP)-induced bladder inflammation to identify and characterize bladder PDGFR alpha+ cells that become myofibroblasts. We found that suburothelial PDGFR alpha+ cells and detrusor PDGFR alpha+ cells display different gene expression profiles. Suburothelial PDGFR alpha+ cells are more abundant than detrusor PDGFR alpha+ cells and express higher levels of fibrosis-related genes. CYP-treatment increased the number of suburothelial PDGFR alpha+ cells, increased Pdgfra, Col1a1, and Fn1 transcription in suburothelial PDGFR alpha+ cells, and increased alpha-smooth muscle actin, collagen, and fibronectin protein expression. CYP-treatment likely activated TNF-alpha and TGF-ss pathways, as indicated by nuclear translocation of SMAD2, SMAD3, and NF kappa B. In conclusion, we identify suburothelial PDGFR alpha+ cells as the fibroblast population which convert into myofibroblasts via activation of TNF-alpha and TGF-ss signaling pathways, due to bladder inflammation.

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