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Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis.

Kim MD, Kim SS, Cha HY, Jang SH, Chang DY, Kim W, Suh-Kim H, Lee JH - Exp. Mol. Med. (2014)

Bottom Line: Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF-bb and TGF-β1 were significantly decreased after MSC/HGF therapy.Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP-13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced.In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biochemistry, Ajou University School of Medicine, Suwon, Republic of Korea [2] Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Republic of Korea.

ABSTRACT
Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to be beneficial for the treatment of liver fibrosis. Here, we investigated the use of genetically engineered MSCs that overexpress hepatocyte growth factor (HGF) as a means to improve their therapeutic effect in liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. HGF-secreting MSCs (MSCs/HGF) were prepared by transducing MSCs with an adenovirus carrying HGF-encoding cDNA. MSCs or MSCs/HGF were injected directly into the spleen of fibrotic rats. Tissue fibrosis was assessed by histological analysis 12 days after stem cell injection. Although treatment with MSCs reduced fibrosis, treatment with MSCs/HGF produced a more significant reduction and was associated with elevated HGF levels in the portal vein. Collagen levels in the liver extract were decreased after MSC/HGF therapy, suggesting recovery from fibrosis. Furthermore, liver function was improved in animals receiving MSCs/HGF, indicating that MSC/HGF therapy resulted not only in reduction of liver fibrosis but also in improvement of hepatocyte function. Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF-bb and TGF-β1 were significantly decreased after MSC/HGF therapy. Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP-13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced. In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF. Thus, MSC/HGF represents a promising approach toward a cell therapy for liver fibrosis.

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Related in: MedlinePlus

Examination of serum parameters. (a, b) Transaminases (ALT and AST), (c) alkaline phosphatase (ALP), (d) ammonia and (e) albumin. Normal rats, N; fibrotic control animals, S; fibrotic animals transplanted with MSCs, M, or MSCs/HGF, H. Data represent the mean±s.d. for each group (*P<0.05, **P<0.01, ***P<0.005).
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fig3: Examination of serum parameters. (a, b) Transaminases (ALT and AST), (c) alkaline phosphatase (ALP), (d) ammonia and (e) albumin. Normal rats, N; fibrotic control animals, S; fibrotic animals transplanted with MSCs, M, or MSCs/HGF, H. Data represent the mean±s.d. for each group (*P<0.05, **P<0.01, ***P<0.005).

Mentions: We next evaluated the effects of cell transplantation on the extent of liver injury and liver function. Serum transaminase levels, which increase when the liver is damaged, were significantly attenuated in the MSC/HGF group (Figures 3a and b), as were ALP levels, which increase when biliary epithelial cells are damaged (Figure 3c), compared with the MSC group and saline control group, demonstrating that MSCs/HGF were more effective in preventing liver damage associated with fibrosis. Similarly, the serum ammonia level, which is an indicator of urea cycle function in hepatocytes, was normalized in the MSC/HGF group to a greater extent than in the MSC group (Figure 3d). In addition, the serum albumin level, which is an indicator of liver function, was slightly increased in the MSC/HGF group but not in the MSC or saline control group (P<0.05; Figure 3e). Taken together, our data demonstrate that MSCs/HGF are more beneficial than MSCs alone with respect to the attenuation of liver damage and recovery of liver function.


Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis.

Kim MD, Kim SS, Cha HY, Jang SH, Chang DY, Kim W, Suh-Kim H, Lee JH - Exp. Mol. Med. (2014)

Examination of serum parameters. (a, b) Transaminases (ALT and AST), (c) alkaline phosphatase (ALP), (d) ammonia and (e) albumin. Normal rats, N; fibrotic control animals, S; fibrotic animals transplanted with MSCs, M, or MSCs/HGF, H. Data represent the mean±s.d. for each group (*P<0.05, **P<0.01, ***P<0.005).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150933&req=5

fig3: Examination of serum parameters. (a, b) Transaminases (ALT and AST), (c) alkaline phosphatase (ALP), (d) ammonia and (e) albumin. Normal rats, N; fibrotic control animals, S; fibrotic animals transplanted with MSCs, M, or MSCs/HGF, H. Data represent the mean±s.d. for each group (*P<0.05, **P<0.01, ***P<0.005).
Mentions: We next evaluated the effects of cell transplantation on the extent of liver injury and liver function. Serum transaminase levels, which increase when the liver is damaged, were significantly attenuated in the MSC/HGF group (Figures 3a and b), as were ALP levels, which increase when biliary epithelial cells are damaged (Figure 3c), compared with the MSC group and saline control group, demonstrating that MSCs/HGF were more effective in preventing liver damage associated with fibrosis. Similarly, the serum ammonia level, which is an indicator of urea cycle function in hepatocytes, was normalized in the MSC/HGF group to a greater extent than in the MSC group (Figure 3d). In addition, the serum albumin level, which is an indicator of liver function, was slightly increased in the MSC/HGF group but not in the MSC or saline control group (P<0.05; Figure 3e). Taken together, our data demonstrate that MSCs/HGF are more beneficial than MSCs alone with respect to the attenuation of liver damage and recovery of liver function.

Bottom Line: Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF-bb and TGF-β1 were significantly decreased after MSC/HGF therapy.Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP-13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced.In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biochemistry, Ajou University School of Medicine, Suwon, Republic of Korea [2] Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Republic of Korea.

ABSTRACT
Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to be beneficial for the treatment of liver fibrosis. Here, we investigated the use of genetically engineered MSCs that overexpress hepatocyte growth factor (HGF) as a means to improve their therapeutic effect in liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. HGF-secreting MSCs (MSCs/HGF) were prepared by transducing MSCs with an adenovirus carrying HGF-encoding cDNA. MSCs or MSCs/HGF were injected directly into the spleen of fibrotic rats. Tissue fibrosis was assessed by histological analysis 12 days after stem cell injection. Although treatment with MSCs reduced fibrosis, treatment with MSCs/HGF produced a more significant reduction and was associated with elevated HGF levels in the portal vein. Collagen levels in the liver extract were decreased after MSC/HGF therapy, suggesting recovery from fibrosis. Furthermore, liver function was improved in animals receiving MSCs/HGF, indicating that MSC/HGF therapy resulted not only in reduction of liver fibrosis but also in improvement of hepatocyte function. Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF-bb and TGF-β1 were significantly decreased after MSC/HGF therapy. Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP-13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced. In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF. Thus, MSC/HGF represents a promising approach toward a cell therapy for liver fibrosis.

Show MeSH
Related in: MedlinePlus