| Co-Investigator(Kenkyū-buntansha) |
NAMHO Huh Okayama University, Department of Cell Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Professor (70173573)
SAKAGUCHI Masakiyo Okayama University, Department of Cell Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Research Associate (70379840)
娜依拉 馬合木提 岡山大学, 大学院・医歯薬学総合研究科, 外国人客員研究員 (90423342)
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| Budget Amount *help |
¥3,860,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
Transplantation of hepatocytes or hepatocyte-like cells of extrahepatic origin is a promising strategy for treatment of acute and chronic liver failure. We examined possible utility of hepatocyte-like cells induced from bone marrow cells for such a purpose. We established a clonal cell line rBM25/S3 from rat bone marrow. The cells grew rapidly (doubling time,〜24 hours) without any appreciable changes in cell properties for at least 300 PDL over a period of 300 days, keeping normal diploid karyotype. The cells expressed CD29, CD44, CD49b, CD90, vimentin and fibronectin but not CD45, indicating that they are of mesenchymal cell origin. When plated on Matrigel with HGF and FGF-4, the cells efficiently differentiated into hepatocyte-like cells that expressed albumin, CYP1A1, CYP1A2, G6Pase, TO, TAT, HNFlα, and HNF4α. When cultivated in the same medium but on a collagen matrix, the cells prominently exhibited adipogenic properties, such as progressive accumulation of lipid droplets in the cytoplasm and expression of adiponectin, leptin and resistin.
We intrasplenically transplanted the three types of cells into rats before 90% hepatectomy to induce fatal liver failure, or rats before and after initiation of CC1_4 treatment to induce liver fibrosis. Intrasplenic transplantation of hepatocyte-like cells rescued 5 out of 15 rats with,fatal liver failure. Furthermore, transplantation of undifferentiated rBM25/S3 cells most effectively suppressed liver fibrosis, followed by those of the adipogenic cells and the hepatogenic cells. Expression of MMP-2 and MMP-9 was also highest in undifferentiated rBM25/S3 cells.
In conclusion, the bone marrow-derived clonal stem cell line (rBM25/S3) is suitable to treat liver fibrosis and the hepatogenically-differentiated derivative is potent to rescue liver failure. So we will further examine effects of combined transplantation of the different cell types of the same clonal origin on treatment of acute and chronic liver failure.
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