Mesenchymal Stem Cells Overexpressing Hepatocyte Growth Factor (HGF) Inhibit Collagen Deposit and Improve Bladder Function in Rat Model of Bladder Outlet Obstruction

Abstract

Bladder outlet obstruction (BOO) caused by collagen deposit is one of the most common problems in elderly male. This study was performed to examine the capability of human mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF) to inhibit collagen deposition in rat model of bladder outlet obstruction (BOO). HGF is known for its antifibrotic effect and the most promising agent for treating bladder fibrosis. BM3.B10 stable immortalized human MSC line (B10) was transduced to encode human HGF with a retroviral vector was prepared (B10.HGF). Two weeks after the onset of BOO. B10, and B10.HGF cells were injected into the rat's bladder wall. After 4 weeks, bladder tissues were harvested and Masson's trichrome staining was performed. Transgene expression in HGF-expressing B10 cells was demonstrated by reverse transcriptase polymerase chain reaction and immunohistochemical staining, and the high levels of HGF secreted by B10. HGF cells was confirmed by ELISA. The mean bladder weight in BOO rats was 5.8 times of the normal controls, while in animals grafted with B10.HGF cells, the weight was down to four times of the control [90.2 +/- 1.6 (control), 89.9 +/- 2.8 (sham), 527.9 +/- 150.9 (BOO), 447.7 +/- 41.0 (BOO + B10), and 362.7 +/- 113.2 (BOO + B10. HGF)]. The mean percentage of collagen area increased in BOO rats, while in the animals transplanted with B10.HGF cells, the collagen area decreased to the normal control level [12.2 > 1.3, (control), 12.8 +/- 1.1 (sham), 26.6 +/- 2.7 (BOO), 19.9 +/- 6.0 (BOO + B10), and 13.3 +/- 2.1 (BOO + B10.HGF)]. The expression of collagen and TGF-beta protein increased after BOO, while the expression of HGF and c-met protein increased in the group with B10.HGF transplantation after BOO. Intercontraction interval decreased after BOO, but it recovered after B10.HGF transplantation. Maximal voiding pressure (MVP) increased after BOO, and it recovered to levels of the normal control after transplantation of B10.HGF cells. Residual urine volume (RU) increased after BOO, but the RU increase was not reversed by transplantation of B10.HGF cells. Human MSCs overexpressing HGF inhibited collagen deposition and improved cystometric parameters in bladder outlet obstruction of rats. The present study indicates that transplantation of MSCs modified to overexpress HGF could serve as a novel therapeutic strategy against bladder fibrosis in patients with bladder outlet obstruction.