Antifibrotic Effect of Hepatocyte Growth Factor-Expressing Mesenchymal Stem Cells in Small-for-Size Liver Transplant Rats

Abstract

Ischemia-reperfusion and chronic injuries associated with small-for-size liver transplantation (SFSLT) impair the regeneration of liver graft and induce liver fibrosis. Mesenchymal stem cells (MSCs) can prevent the development of liver fibrosis, and hepatocyte growth factor (HGF) can also attenuate liver cirrhosis. Our previous studies have demonstrated that higher occurrence of liver fibrosis existed in rats post-SFSLT, and that implantation of HGF/MSCs, the human HGF (hHGF)-expressing MSCs, can improve liver regeneration, reduce mortality of rats, as well as have the potent antifibrotic effect in this SFSLT model. In the present study, we implanted HGF/MSCs into liver grafts via the portal vein and investigated their role in antifibrosis effect, using a 30% SFSLT rat model. Fibrosis indexes, including laminin (LN), hyaluronic acid (HA) levels in serum and hydroxyproline (Hyp) content in the liver grafts, the expression of transforming growth factor-beta1 (TGF-beta(1)), rat HGF (rHGF), alpha-smooth muscle actin (alpha-SMA) in hepatic stellate cells (HSCs), alanine aminotransferase (ALT), total bilirubin (BIL), and albumin (ALB) levels in serum, in rats in different treatment groups were assessed at different time points. We found that HGF/MSCs significantly inhibited the formation of liver fibrosis in rats undergoing SFSLT, while MSCs and HGF had synergistic effects in the process. The antifibrosis effect of HGF/MSCs may have contributed in modulating the activation and apoptosis of HSCs, elevating the rHGF expression level, and decreasing the TGF-beta(1) secretion of activated HSCs. These studies suggest that HGF/MSCs may be a novel therapeutic option for the treatment of liver fibrosis after SFSLT.

Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

“…Recent studies demonstrate that HGF reduces fibrogenesis by not only inhibiting TGF-b signalling but also down-regulating TGF-b in several experimental models of fibrosis [10,15,49,51,52]. In the present study, the production of TGF-b1 was downregulated after apoptotic cell instillation during the late fibrotic phases (days 14 and 21 after bleomycin), while the HGF production continuously increased and peaked at 21 days, indicating that the antifibrotic action in the BLM+ApoJ group is concordant with an increase in HGF and a decrease in TGF-b1 levels as compared with the BLM+Sal group.…”

Activity of mesenchymal stem cells in therapies for chronic skin wound healing

“…Aside from IL-10, HGF is a major contributor to reduced fibrosis, which has been shown to be effective in advancing clean wound healing in a variety of tissues such as liver 94 and various skin contexts. 95,96 HGF has also been attributed to chronic wounds, with differential regulation of HGF production and presence of c-Met in chronic wound dermis.…”

The use of mesenchymal stromal cells in solid organ transplantation

“…Moreover, HGF enhanced the incorporation of MSCs into injured livers, and the engrafted cells and their progeny produced albumin [55]. In another study the same group showed that HGF-expressing MSCs significantly inhibited the formation of liver fibrosis in rats undergoing small-for-size rat LT with synergistic effects of the MSCs and HGF [56].…”

“…56.6 Mesenchymal stromal cell administration in solid organ transplantation 56.6.1 Kidney transplantation Kidney transplantation is the best option for patients suffering from end-stage kidney diseases, improving survival and quality of life compared with maintenance dialysis [28,29]. The site of placement of a transplanted kidney is shown in Figure 56.1.…”