Molecular Mechanisms Driving Chemokine-mediated Prostate Myofibroblast Phenoconversion.

[摘要] Benign prostate hyperplasia (BPH), a proliferative condition of the prostate common in aging in men, and smooth muscle hypercontractility are associated with urinary voiding dysfunction (LUTD) manifest as Lower Urinary Tract Symptoms (LUTS). However, work from our laboratory has revealed that tissue fibrosis may also be an important and previously unrecognized pathobiology contributing to LUTD. Tissue fibrosis arises from the differentiation of fibroblasts or other progenitor cells into myofibroblasts, which then produce and secrete collagens and fibronectins that augment and remodel the extracellular matrix(ECM). In this dissertation we report that diet-induced obesity and associated tissue inflammation, can drive prostatic fibrosis and LUTS in an aging accelerated mouse model. We also report that, although myofibroblast differentiation is commonly associated with activation of the TGFB/TGFBRI axis, pro-inflammatory chemokine CXCL12/CXCR4-mediated signaling can promote myofibroblast phenoconversion through non-canonical EGFR-coupled pathways that do not depend on TGFB/TGFBRI axis activation or Smad signaling. Furthermore, we show through RNASeq approaches that CXCL12/CXCR4 and TGFB/TGFBRI induce largely similar transcriptional signatures during prostate myofibroblast phenoconversion. One key difference, however, is that CXCL12/CXCR4 axis activation induced the gene transcription and protein expression of cullins, which play key roles in collagen export. Therefore, activation of the CXCL12/CXCR4 axis may promote fibrosis both through increased collagen production and collagen transport into the ECM. Taken altogether, the data presented in this dissertation provides solid evidence in support of fibrosis as one of the contributors to LUTS, and provides detailed analysis on how pro-inflammatory proteins secreted by prostate fibroblasts promote myofibroblasts phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis and treatment of LUTS.

[发布机构] University of Michigan

[效力级别] CXC-type chemokine

[关键词] fibrosis;CXC-type chemokine;prostate;Diabetes;Lower Urinary Tract Dysfunction (LUTD);Molecular;Cellular and Developmental Biology;Science;Cellular and Molecular Biology