Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice
Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice
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DOI：
10.1002/hep.20452
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发表时间：
2004-12-01
期刊：
影响因子：
13.5
通讯作者：
Okita, K
中科院分区：
文献类型：
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作者：
Sakaida, I;Terai, S;Okita, K
我们研究了骨髓细胞（BMC）移植对已建立的肝纤维化的影响。通过尾静脉将绿色荧光蛋白（GFP）小鼠的BMC移植到四氯化碳（CCl 4）处理4周的C57 BL 6小鼠中，并且用CCl 4再处理小鼠4周（总共8周）。天狼星红和绿色荧光蛋白（GFP）染色清楚显示迁移的BMCs与纤维沿着存在，抗MMP-9抗体和原位杂交显示MMP-9的强表达。双荧光免疫组化显示MMP-9在GFP阳性细胞表面表达。电影原位酶谱分析显示，在门静脉周围区与MMP-9阳性的BMC的位置相一致的明胶酶活性强。BMC移植后4周，与仅用CCl 4处理的小鼠相比，小鼠的肝纤维化显著减少，如通过肝脏的羟脯氨酸含量所评估的。Liv 8阴性的BMCs亚群负责这种纤维溶解作用。总之，与仅用CCl 4治疗的小鼠相比，连续注射CCl 4的BMC移植小鼠的肝纤维化减少，BMC移植后的存活率显著提高。这一发现为肝纤维化的治疗提供了新的思路。
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 metalloproteinase (MMP)-9 shown by anti-MMP-9 antibodies and in situ hybridization. Double 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 conclusion, 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.