Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes

Abstract

We have developed an in vivo mouse model, the green fluorescent protein (GFP)/carbon tetrachloride (CCl(4)) model, and have previously reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes via hepatoblast intermediates. Here, we have investigated the growth factors that are closely related to the differentiation of transplanted BMCs into hepatocytes, and the way that a specific growth factor affects the differentiation process in the GFP/CCl(4) model. We performed immunohistochemical analysis to identify an important growth factor in our model, viz., fibroblast growth factor (FGF). In liver samples, the expression of FGF1 and FGF2 and of FGF receptors (FGFRs; FGFR1, FGFR2) was significantly elevated with time after bone marrow transplantation (BMT) compared with other factors, and co-expression of GFP and FGFs or FGFRs could be detected. We then analyzed the effect and molecular mechanism of FGF signaling on the enhancement of BMC differentiation into hepatocytes by immunohistochemistry, immunoblotting, and microarray analysis. Treatment with recombinant FGF (rFGF), especially rFGF2, elevated the repopulation rate of GFP-positive cells in the liver and significantly increased the expression of both Liv2 (hepatoblast marker) and albumin (hepatocyte marker). Administration of rFGF2 at BMT also raised serum albumin levels and improved the survival rate. Transplantation of BMCs with rFGF2 specifically activated tumor necrosis factor-alpha (TNF-alpha) signaling. Thus, FGF2 facilitates the differentiation of transplanted BMCs into albumin-producing hepatocytes via Liv2-positive hepatoblast intermediates through the activation of TNF-alpha signaling. Administration of FGF2 in combination with BMT improves the liver function and prognosis of mice with CCl(4)-induced liver damage.

Differentiation of embryonic stem cells into hepatocytes that coexpress coagulation factors VIII and IX

“…Our previous study and those of others have demonstrated that sodium butyrate, an inhibitor of histone deacetylase, induces the differentiation of ES cells into hepatocytes [12][13][14][15] . Some researchers have also shown that at the time of liver specification, BMP4 expression in the mesoderm surrounding the foregut endoderm is required for the induction of hepatic fate [18][19][20] and that bFGF from the cardiac mesoderm is required for the initiation of liver bud development in the anterior definitive endoderm [21,22] . Zhou [23] have reported a synergistic effect between bFGF and BMP4 in inducing hepatocyte differentiation.…”

“…Studies have shown that at the time of liver specification, the induction of hepatic fate requires BMP4 expression in the mesoderm surrounding the foregut endoderm [18][19][20] . Derived from the cardiac mesoderm, bFGF is required for the initiation of liver bud development in the anterior definitive endoderm [21,22] . Additional studies have indicated a synergistic effect between BMPs and FGFs in inducing hepatocyte differentiation [23] .…”

Células tronco mesenquimais derivadas de tecido adiposo no tratamento de cirrose hepática

“…Um dos principais fatores de crescimento utilizados em cultura é o fator de crescimento do fibroblasto (FGF), um importante mitógeno que já se demonstrou importante no desenvolvimento hepático (ISHIKAWA et al, 2006). Neste sentido, foi demonstrado através de ensaio imunoenzimático que o transplante de AD-MSCs pré--tratadas com fator de crescimento fibroblástico básico (bFGF) em ratos com lesão hepática, induzida por CCl 4 durante oito semanas, atenua a fibrose hepática através do aumento da expressão de metaloproteinases (KAMADA et al, 2009).…”

Potential of Mesenchymal Stem Cells for Liver Regeneration

“…Based on these promising characteristics, MSC have now been tested in a wide variety of injury/disease model systems for their ability to generate hepatocytes and correct these liver defects. Using MSC isolated from a variety of mouse, rat, and human tissues, investigators have now provided evidence that MSC can mediate varying degrees of correction/repair of the liver following injury due to partial hepatectomy [126,[130][131][132][133], treatment with the toxin CCl4 [134][135][136][137][138][139][140][141][142][143][144][145], injury induced by allylalcohol [146,147], and treatment with 2-acetylaminofluorene [139].…”