The Therapeutic Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Simvastatin in a Rat Model of Liver Fibrosis

Abstract

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Studies concerning the capacity of mesenchymal stem cells (MSCs) and simvasatain (SIMV) to repair fibrotic tissues through reducing inflammation, collagen deposition, are still controversial. This study aimed to investigate the therapeutic efficacy of bone marrow (BM)-derived MSCs and SIMV on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats were divided into: normal, CCl4, CCl4/MSCs, CCl4/SIMV, CCl4/MSCs/SIMV, and SIMV groups. BM-derived MSCs were detected by RT-PCR of CD29 and were then infused into the tail vein of female rats that received CCl4 injection to induce liver fibrosis. Sex-determining region Y (SRY) gene on Y-chromosome gene was assessed by PCR to confirm homing of the male stem cells in liver tissue of the female recipients. Serum liver function tests, liver procollagens I and III, tissue inhibitors of metalloproteinase-1 (TIMP-1), endoglin, matrix metalloproteinase-1 (MMP-1) gene expressions, transforming growth factor-beta (TGF-β1) immunostaining, and histopathologicl examination were performed. MSCs and SIMV decreased liver procollagens I and III, TIMP-1 and endoglin gene expressions, TGF-β1 immunostaining, and serum liver function tests compared with the CCl4 group. MMP-1 expression was increased in the CCl4/MSCs group. Histopathological examination as well as fibrosis score supports the biochemical and molecular findings. It can be concluded that MSCs and SIMV were effective in the treatment of hepatic CCl4-induced fibrosis-rat model. Treatment with MSCs was superior to SIMV. This antifibrotic effect can be attributed to their effect on the MMPs/TIMPs balance which is central in fibrogenesis.

Mesenchymal stromal cells and liver fibrosis: a complicated relationship

“…Motawi et al . (92) also established that MSCs administered at the cessation of injury can lead to a reduction in fibrosis and allied this to a significant increase in MMP‐1 ( P < 0.01) and a decrease in TIMP‐1 ( P < 0.001). They administered syngeneic BM‐MSCs via the tail vein of CCl 4 ‐injured rats (intraperitonially twice a week for 6 wk) 1 d after the cessation of injury and analyzed the effects 8 d later.…”

“…It is not possible to extract a consistent profile of effects on MMPs as a result of inconsistencies in what has been tested. Nevertheless, syngeneic rodent MSC treatment in models of CCl 4 ‐induced liver injury leads to increased expression of MMP‐1/13 (78, 79, 92) and MMP‐12 (83), a reduction in expression of MMP‐2 (84, 86), and no or limited effect on MMP‐9 (78, 83, 86) in the setting of resolving fibrosis. What remains unclear is whether these fluxes in MMPs reflect maturation/changes in the inflammatory infiltrate (45, 97), including HSCs, neutrophils, macrophages, and dendritic cells (driven by MSCs), or whether MSCs actually secrete MMPs themselves.…”

KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins

“…Simvastatin, through the activation of the endothelial KLF2-nitric oxide pathway, is the most effective statin protecting the hepatic endothelium in cirrhosis 13. Moreover, previous reports suggested that statins may improve HSC phenotype,6 14 15 however, the possible direct role of KLF2 improving HSC function and liver fibrosis has never been investigated.…”

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

“…However, due to small numbers of heterogene- to CCl4-treated rats (Jung et al 2009;Li et al 2013;Seo et al 2014) Reduced fibrosis, TGF-β, EMT, and improved liver function UC-MSC transfusion in PBC patients with an incomplete response to UDCA No obvious side effects Bone marrow-derived mesenchymal stem cells (BMMSCs) in CCl4-treated rats (Motawi et al 2014) Reduced fibrosis markers and inflammatory cytokines BM-MSCs in patients with alcoholic cirrhosis (Jang et al 2014) No significant side effects. Histological improvement, reduced TGF-β, collagen I, α-SMA (c) Antagonizing TGF-β and CTGF EW-7197 in CCl4-treated mouse, BDL rat, bleomycin mouse, and unilateral ureteral obstruction mouse models (Park et al 2014) Attenuated myofibroblast activation and ECM accumulation, blockade TGF-β1/Smad2/3 and ROS signaling Not applied for liver fibrosis Human bone morphogenic protein-7 (rhBMP-7) in porcine serum-treated rats (Zhong et al 2013 ous patients tested, the potential effects of this therapy remain unclear (Pellicoro et al 2014).…”

“…A pilot study investigated the safety and efficacy of UC-MSC transfusion in primary biliary cirrhosis (PBC) patients and indicated that UC-MSC transfusion is feasible and well tolerated in patients . The other study indicated that transplantation of bone marrow-derived mesenchymal stem cell (BM-MSC) therapy for the treatment of liver fibrosis in CCl4-treated rats is effective (Motawi et al 2014). Additionally, the clinical therapy in patients with alcoholic cirrhosis using BM-MSC induced a histological and quantitative improvement in hepatic fibrosis (Jang et al 2014).…”