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）移植对已形成的肝纤维化的影响。将绿色荧光蛋白（GFP）小鼠的BMC通过尾静脉移植到四氯化碳（CCl_4）处理4周的C57BL6小鼠中，并用CCl_4再处理小鼠4周（总共8周）。天狼星红和 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基质金属蛋白酶 (MMP)-9 强表达。双荧光免疫组化显示GFP阳性细胞表面有MMP-9表达。胶片原位酶谱分析显示门静脉周围区域具有强烈的明胶分解活性，与 MMP-9 阳性 BMC 的位置一致。 BMC 移植后 4 周，根据肝脏羟脯氨酸含量评估，与单独使用 CCl_4 治疗的小鼠相比，小鼠的肝纤维化显着减少。 Liv8 阴性 BMC 亚群是造成这种纤维溶解作用的原因。总之，与单独使用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程度减轻，BMC移植后的存活率显着提高。这一发现为肝纤维化的治疗引入了新概念。还已知预防纤维化可以减少癌发生。因此，这些结果可能表明纤维溶解骨髓细胞移植可以预防肝癌发生。

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