Novel anti-fibrotic modalities for liver fibrosis: Molecular targeting and regenerative medicine in fibrosis therapy

Based on the cellular and molecular mechanisms underlying hepatic fibrogenesis, several kinds of approaches have been proposed to treat liver fibrosis. Among a number of growth factors and cytokines that regulate collagen metabolism, transforming growth factor (TGF)‐β is the most potent factor to ac...

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Bibliographic Details
Published in:Journal of gastroenterology and hepatology 2012-03, Vol.27 (s2), p.85-88
Main Authors: Inagaki, Yutaka, Higashiyama, Reiichi, Higashi, Kiyoshi
Format: Article
Language:English
Subjects:
Animals
bone marrow
Bone Marrow Cells - drug effects
Bone Marrow Cells - metabolism
Cell Movement - drug effects
collagen
Genetic Therapy
Humans
Liver Cirrhosis - genetics
Liver Cirrhosis - metabolism
Liver Cirrhosis - pathology
Liver Cirrhosis - therapy
liver fibrosis
Liver Regeneration - drug effects
Liver Regeneration - genetics
Molecular Targeted Therapy
Regenerative Medicine
Signal Transduction - drug effects
Signal Transduction - genetics
Smad
Smad Proteins - genetics
Smad Proteins - metabolism
Transforming Growth Factor beta - genetics
Transforming Growth Factor beta - metabolism
transforming growth factor-β
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Summary:Based on the cellular and molecular mechanisms underlying hepatic fibrogenesis, several kinds of approaches have been proposed to treat liver fibrosis. Among a number of growth factors and cytokines that regulate collagen metabolism, transforming growth factor (TGF)‐β is the most potent factor to accelerate liver fibrosis by activating hepatic stellate cells, stimulating collagen gene transcription, and suppressing matrix metalloproteinases expression. Thus, TGF‐β as well as its intracellular mediators, Smad proteins, can be potential therapeutic targets for liver fibrosis. Constitutive phosphorylation and nuclear accumulation of Smad3 is the common feature of activated stellate cells. We have synthesized a novel small compound that inhibits Smad3‐dependent collagen gene transcription by promoting nuclear import of a transcriptional repressor, YB‐1. Another insight into anti‐fibrotic strategies is the contribution of bone marrow‐derived cells to the regression of liver fibrosis. Administration of granulocyte‐colony stimulating factor enhanced the migration of bone marrow‐derived cells into fibrotic liver tissue and accelerated the regression of experimental liver fibrosis. We have recently identified novel unknown factors expressed by bone marrow‐derived cells that not only ameliorate liver fibrosis but also accelerate regeneration of fibrotic liver.
ISSN:0815-9319
1440-1746
DOI:10.1111/j.1440-1746.2011.07006.x