The development of cell therapy for liver fibrolysis and prevention of carcinogenesis using bone marrow cell transplantaion

利用骨髓细胞移植治疗肝纤维化和预防癌变的细胞疗法的发展

• 批准号: 16590597
• 负责人: SAKAIDA Isao
• 金额: $ 2.3万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590597/
• 关键词: bone marrow cell; stem cell; extracellular matrix; preneoplastic lesion; cancer; 肝線維化; 前癌性病変; GFP; CC14 model; MMP-9; MMP-14

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 (CCl_4)-treated C57BL6 mice through the tail vein, and the mice were treated for 4 more weeks with CCl_4 (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 CCl_4 alone. Subpopulation of Liv8-negative BMCs was responsible for this fibrolytic effect. In conclusion, mice with BMC transplants with continuous CCl_4 injection had reduced liver fibrosis and a significantly improved survival rate after BMC transplantation compared with mice treated with CCl_4 alone. This finding introduces a new concept for the therapy of liver fibrosis. Also it has been known that prevention of fibrosis may reduce the carcinogenesis. Thus these results may suggest that fibrolysis bone marrow cell transplantation leads prevention of hepato-carcinogenesis.

我们研究了骨髓细胞（BMC）移植对已建立的肝纤维化的影响。将绿色荧光蛋白（GFP）小鼠的BMC通过尾静脉移植到4周碳四氯化碳（CCL_4）处理的C57BL6小鼠中，并用CCL_4（总计8周）将小鼠治疗4周。 Sirius Red和GFP染色清楚地表明迁移的BMC与纤维一起存在，抗MMP-9抗体和原位杂交显示了基质金属蛋白酶（MMP）-9的强烈表达。双荧光免疫组织化学在GFP阳性细胞表面上显示了MMP-9的表达。薄膜原位动态分析表明，与MMP-9阳性BMC的位置相吻合的周围区域中的明胶活性很强。 BMC移植后四个星期，与单独用CCL_4治疗的小鼠相比，通过肝脏的羟基含量评估，小鼠的肝纤维化显着降低。 LIV8阴性BMC的亚群负责这种纤维化效应。总之，与单独使用CCL_4治疗的小鼠相比，具有连续CCL_4注射BMC移植的小鼠肝纤维化降低，BMC移植后的存活率显着提高。这一发现引入了一种用于治疗肝纤维化的新概念。同样众所周知，预防纤维化可能会减少癌变。因此，这些结果可能表明纤维化骨髓细胞移植会导致预防肝癌发生。

项目成果

Clinical application of bone marrow cell transplantation for liver diseases.

骨髓细胞移植治疗肝病的临床应用。

• 发表时间: 2006
• 期刊: J Gastroenterol 41(1)
• 作者: Laviano A;Meguid MM;Inui A;Muscaritoli M;Rossi-Fanelli F;Sakaida I
• 通讯作者: Sakaida I

A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver.

• DOI: 10.1016/j.bbrc.2003.12.044
• 发表时间: 2004-01
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: N. Yamamoto;S. Terai;Shinya Ohata;Tomomi Watanabe;K. Omori;K. Shinoda;K. Miyamoto;T. Katada;I. Sakaida;H. Nishina;K. Okita

Human homologue of maid is a useful marker protein in hepatocarcinogenesis

• DOI: 10.1053/j.gastro.2005.03.014
• 发表时间: 2005-05-01
• 期刊: GASTROENTEROLOGY
• 影响因子: 29.4
• 作者: Takami, T;Terai, S;Okita, K
• 通讯作者: Okita, K

Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes

• DOI: 10.1007/s00441-005-0077-0
• 发表时间: 2006-02-01
• 期刊: CELL AND TISSUE RESEARCH
• 影响因子: 3.6
• 作者: Ishikawa, T;Terai, S;Okita, K
• 通讯作者: Okita, K

新規肝細胞癌の腫瘍マーカー抗HHMIgGの発見

新型肝癌肿瘤标志物抗HHMIgG的发现

• 发表时间: 2004