2003 Fiscal Year Final Research Report Summary
The analysis for proliferation and differentiation of hepatic stem cells
| Project/Area Number |
13470121
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Yamaguchi University |
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Principal Investigator |
OKITA Kiwamu Yamaguchi University, School of Medicine Department of Gastroenterlogy & Hepatlogy, Professor, 医学部, 教授 (70107738)
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| Co-Investigator(Kenkyū-buntansha) |
TERAI Shuji Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (00332809)
SAKAIDA Isao Yamaguchi University, School of Medicine, Associate Professor, 医学部, 講師 (80263763)
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| Project Period (FY) |
2001 – 2003
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| Keywords | Hepatic stem cell / Differentiation / Cancer stem cell / Extra cellular matrix / Hepatocarcinogeneisis / Bone marrow cell / Niche / Cell therapy |
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| Research Abstract |
Here we found that persistent injury induced efficient trans-differentiation of BMCs into functional hepatocytes. Liver cirrhosis mice induced by carbon tetrachloride were injected with 1x10^5 non-treated green fluorescent protein (GFP)-positive BMCs via tall vein. In these mice, transplanted GFP-positive BMCS efficiently migrated into the peri-portal area of liver lobules after one day and repopulated one-fourth of the recipient liver by 4 weeks. In contrast, no GFP-positive BMCs were detected following transplantation into control mice. with undamaged livers. BMCs trans-differentiated into functional mature hepatocytes via immature hepatoblasts. Serum albumin was significantly elevated to compensate for chronic liver failure by BMC transplantation. These results showed that the recipient condition and microenvironments are key factors for successful cell therapy using BMC. We named this model as a GFP/CC14 model. As the next step, we developed a new monoclonal antibody, anti-Liv8 usi
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ng mouse fetal liver antigen. On embryonic day 11.5, Liv8-positive cells were seen in the liver of wild-tape, but not AML1 knockout mice, which lack the hematopoietic system. Liv8-positive cells accounted for 32% of the BMC in adult mice and included CD45-positive cells. We separated Liv8-positive or Liv8-negative cells using Auto Magnetic Cell Sorting system, and then transplanted these cells to a continuous liver damaged model. After one week, there was no marked difference in the initial colonization of BMC in the liver between recipients of Liv8-positive and Liv8-negative cells, but at 4 weeks more efficient BMC trans-differentiation into hepatocytes was seen with Liv8-negative cells. Now we are trying to identify the antigen of anti-Liv8. These analysis will be useful to develop all efficient cell therapy to repair damaged liver. On the other hands, we identified that new protein. Human homologue of maid (HHM) is a helix-loop-helix (HLH) transcriptional regulatory protein that is involved in the hepatic stem cell development and differentlation. We analyzed the potential involvement of HHM in hepatocarcinogenesis. We assessed HHM expression in the chorine deficient L-amino acid defined (CDAA) diet model of rat hepatocarcinogenesis by in situ hybridization DISH), and human HCC samples by immunohistochemical analysis. High HHM expression was seen in foci and HCC. These results suggested that HHM may be a useful marker protein to detect initiation of hepatocarcinogenesis Less
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