Molecular characterization of suburothelial fibrosis in murine acute recurrent bladder inflammation.

Abstract

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 (PDGFRα) 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 PDGFRαcells that become myofibroblasts. We found that suburothelial PDGFRαcells and detrusor PDGFRαcells display different gene expression profiles. Suburothelial PDGFRαcells are more abundant than detrusor PDGFRαcells and express higher levels of fibrosis-related genes. CYP-treatment increased the number of suburothelial PDGFRαcells, increased Pdgfra, Col1a1, and Fn1 transcription in suburothelial PDGFRαcells, and increased α-smooth muscle actin, collagen, and fibronectin protein expression. CYP-treatment likely activated TNF-α and TGF-ß pathways, as indicated by nuclear translocation of SMAD2, SMAD3, and NFκB. In conclusion, we identify suburothelial PDGFRαcells as the fibroblast population which convert into myofibroblasts via activation of TNF-α and TGF-ß signaling pathways, due to bladder inflammation.