2004Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice.pdf

Transplantation of Bone Marrow Cells Reduces CCl4- Induced Liver Fibrosis in Mice Isao Sakaida,1 Shuji Terai,1 Naoki Yamamoto,1 Koji Aoyama,1 Tsuyoshi Ishikawa,1 Hiroshi Nishina,2 and Kiwamu Okita1 We investigated the effect of bone marrow cell (BMC) transplantation on established liver fibrosis. BMCs of green fluorescent protein (GFP) mice were transplanted into 4-week carbon tetrachloride (CCl4)–treated C57BL6 mice through the tail vein, and the mice were treated for 4 more weeks with CCl4 (total, 8 weeks). Sirius red and GFP staining clearly indicated migrated BMCs existing along with fibers, with strong expression of matrix met- alloproteinase (MMP)-9 shown by anti–MMP-9 antibodies and in situ hybridization. Dou- ble fluorescent immunohistochemistry showed the expression of MMP-9 on the GFP- positive cell surface. Film in situ zymographic analysis revealed strong gelatinolytic activity in the periportal area coinciding with the location of MMP-9–positive BMCs. Four weeks after BMC transplantation, mice had significantly reduced liver fibrosis, as assessed by hydroxyproline content of the livers, compared to that of mice treated with CCl4 alone. Subpopulation of Liv8-negative BMCs was responsible for this fibrolytic effect. In conclu- sion, mice with BMC transplants with continuous CCl4 injection had reduced liver fibrosis and a significantly improved survival rate after BMC transplantation compared with mice treated with CCl4 alone. This finding introduces a new concept for the therapy of liver fibrosis. Supplementary material for this article can be found on the HEPATOLOGY website (/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;40: 1304–1311.) Recent reports have shown the capacity of the bonemarrow cell (BMC) to differentiate into a varietyof non-hematopoietic cell lineages.1–5 These re- sults indicate that the BMC is an attractive cell source for regenerative medicine compared with tissue-specific stem cells.6 The capacity of the BMC to differentiate