Hypothesis / aims of study
Benign prostatic hyperplasia (BPH) shows increases in the proportion of fibrous components as it grows, and patients with abundant fibrous components typically require surgery. Myofibroblasts are reportedly associated with tissue fibrosis in several organs; their differentiation is induced by TGF-β1 and IGFBP3, thereby promoting fibrosis through growth factors or extracellular matrix. However, the process of fibrosis in BPH remains unclear. Therefore, to clarify the mechanisms of prostatic fibrosis in BPH, we analyzed the qualitative and quantitative changes in myofibroblasts during the growth process of BPH using model rat and human BPH tissues.
Study design, materials and methods
Fetal urogenital sinus (UGS) isolated from male 20-day-old rat embryos was implanted into the ventral prostate of pubertal male rats to create rat models of BPH. Using BPH tissues and left ventral prostate as a control, the number of myofibroblasts positive for α-SMA and vimentin was evaluated by immunohistochemical staining. Expression of TGF-β1 and IGFBP3 was also evaluated by western blotting and immunohistochemical staining (n=4). In addition, using BPH model rats at 2 weeks, 3 weeks, and 8 weeks after UGS implantation (n=4), histological and expression analyses were performed with time. Furthermore, the fine morphological characteristics of myofibroblasts were evaluated by electron microscopy using human BPH tissues. For statistical analyses, an un-paired t test was used and p <0.05 was considered to indicate significant differences.
BPH tissues showed a significant increase (9.2%) in the number of myofibroblasts (p<0.05) when compared with normal prostate (4.5%), and these were abundantly located in stromal area (Fig 1,2). Expression of both TGF-β1 and IGFBP3 was significantly up-regulated in BPH (p<0.05). The number of myofibroblasts and the expression of TGF-β1 and IGFBP3 increased time-dependently (p<0.05), and the expression of these growth factors increased ahead of myofibroblasts. Electron microscopy confirmed that the myofibroblast progenitor cells, which possess abundant stress fibers, were predominantly located around fibrous areas in human BPH.
Interpretation of results
These results showed that myofibroblasts works as promotor of fibrosis in the growth of BPH. In addition, it is expected that fibroblast-myofibroblast differentiation was locally activated in BPH tissues. Interestingly, the study of electron microscopy demonstrates the presence of myofibroblast progenitor cells which have characteristics of fibroblasts and myofibroblasts. Although further study needed, myofibroblaast progenitor cells have the possibilities of new therapeutic targets.