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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

Analysis of profibrogenic cytokine expression. (a) Detection of TGF-β1 and PDGF-bb mRNA in individual rats by RT–PCR. (b, c) Mean relative expression levels of TGF-β1 and PDGF-bb in liver tissues from normal rats, N; control fibrotic animals, S; or fibrotic animals transplanted with MSCs, M, or MSC/HGF, H. Data are normalized to GAPDH expression levels and represent the mean±s.d. for each group (*P<0.05, **P<0.01, ***P<0.005).
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fig5: Analysis of profibrogenic cytokine expression. (a) Detection of TGF-β1 and PDGF-bb mRNA in individual rats by RT–PCR. (b, c) Mean relative expression levels of TGF-β1 and PDGF-bb in liver tissues from normal rats, N; control fibrotic animals, S; or fibrotic animals transplanted with MSCs, M, or MSC/HGF, H. Data are normalized to GAPDH expression levels and represent the mean±s.d. for each group (*P<0.05, **P<0.01, ***P<0.005).

Mentions: We next tried to elucidate the mechanistic basis for the enhanced therapeutic effect of transplanted MSCs/HGF. Because HGF was reported to downregulate TGF-β1 and PDGF-bb, we assessed the expression of TGF-β1 and PDGF-bb mRNA in the liver (Figure 5a). Although mRNA levels varied among animals, expression of TGF-β1 and PDGF-bb was significantly increased in fibrotic livers, and this effect was dramatically ameliorated by MSCs/HGF but not by MSCs (Figures 5b and c).


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)

Analysis of profibrogenic cytokine expression. (a) Detection of TGF-β1 and PDGF-bb mRNA in individual rats by RT–PCR. (b, c) Mean relative expression levels of TGF-β1 and PDGF-bb in liver tissues from normal rats, N; control fibrotic animals, S; or fibrotic animals transplanted with MSCs, M, or MSC/HGF, H. Data are normalized to GAPDH expression levels and 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

fig5: Analysis of profibrogenic cytokine expression. (a) Detection of TGF-β1 and PDGF-bb mRNA in individual rats by RT–PCR. (b, c) Mean relative expression levels of TGF-β1 and PDGF-bb in liver tissues from normal rats, N; control fibrotic animals, S; or fibrotic animals transplanted with MSCs, M, or MSC/HGF, H. Data are normalized to GAPDH expression levels and represent the mean±s.d. for each group (*P<0.05, **P<0.01, ***P<0.005).
Mentions: We next tried to elucidate the mechanistic basis for the enhanced therapeutic effect of transplanted MSCs/HGF. Because HGF was reported to downregulate TGF-β1 and PDGF-bb, we assessed the expression of TGF-β1 and PDGF-bb mRNA in the liver (Figure 5a). Although mRNA levels varied among animals, expression of TGF-β1 and PDGF-bb was significantly increased in fibrotic livers, and this effect was dramatically ameliorated by MSCs/HGF but not by MSCs (Figures 5b and c).

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