Administration of fibroblast growth factor 2 in combination with bone marrow transplantation synergistically improves carbon-tetrachloride-induced liver fibrosis in mice

Abstract

We previously reported that fibroblast growth factor 2 (FGF2) facilitated the differentiation of transplanted bone marrow cells (BMCs) into hepatocytes. Our earlier study also demonstrated that administration of FGF2 in combination with bone marrow transplantation (BMT) synergistically activated tumor necrosis factor-alpha signaling and significantly improved liver function and prognosis more than BMT alone. However, the way that it affected the extracellular matrix remained unclear. Here, we investigated the effect of FGF2 treatment together with BMT on liver fibrosis in mice treated with carbon tetrachloride (CCl(4)). Transplantation of BMCs and concurrent treatment with FGF2 caused a statistically significant reduction in CCl(4)-induced liver fibrosis that was accompanied by strong expression of matrix metalloproteinase 9 as compared with FGF2-only treatment or BMT alone. Moreover, in this process, the proliferation of bone-marrow-derived cells was accelerated without causing apoptosis. Thus, the administration of FGF2 in combination with BMT synergistically improves CCl(4)-induced liver fibrosis in mice. This treatment has the potential of being an effective therapy for patients with liver cirrhosis.

Bone Marrow Cell Transplant does Not Prevent or Reverse Murine Liver Cirrhosis

“…It is noteworinjected cells because technetium has a short half-life. Our data, however, are in accord with other studies that thy that tail injection of the same cell fraction in a rat model of myocardial infarction results in detection of demonstrate homing and retention of bone marrowderived cells into the liver after transplant (13,26,39). very low levels of radioactivity in the heart and other cytes in vivo.…”

“…An important question is how effective is the tail vein route in metalloproteases (11,13,38). This observation is important because it bears relevance to cirrhosis resolution.…”

“…Most studies performed with cell therapies in liver Liver cirrhosis is a worldwide prevalent disease that has serious impacts on public health issues. It derives diseases have been restricted to the therapeutic potential of these cells after a single cell infusion in animals with from chronic injury to the liver that is commonly caused by viral hepatitis and alcoholism (1,47,48).an already damaged liver (13,39,51). Nonetheless, liver diseases usually have a chronic course, developing over Despite great regenerative capacity of the liver, successive injuries result in a significant loss of hepatocytes many years before cirrhosis is discovered.…”

“…Measurement of (A) ALT and (B) albumin in postinjury cell infusion group did not show any differences between cell-treated and nontreated groups (ANOVA, followed by Tukey's post test, *** a p < 0.001 when compared to normal group; *** b p < 0.001 and ** b p < 0.01 when compared to values found after 15 weeks of chronic liver injury). utes to tissue regeneration have not been elucidated, but Although some groups have used alternative routes for BMC infusion (2,24,35), most of them use systemic recent reports have shown that BMCs can contribute to tissue remodeling by expressing and releasing matrix transplantation through tail vein (13,39,44). An important question is how effective is the tail vein route in metalloproteases (11,13,38).…”

Delta-like 1 Serves as a New Target and Contributor to Liver Fibrosis Down-regulated by Mesenchymal Stem Cell Transplantation

“…Therefore, we propose that LMW and HMW FGF2 play opposing roles in liver fibrosis, but further studies are required to fully elucidate the role of FGF2. Furthermore, the optimal amount of LMW FGF2 for liver fibrosis therapy must be determined, and the susceptibility should be addressed in different animal models, as different concentrations of FGF2 have shown distinct effects in different animal lines (38). The unique pathological features of liver diseases and the multiple isoforms of FGF2 suggest a complex role for FGF2 in liver pathology.…”