A DEVELOPMENT OF THE HEPATOCYTE TRANSPLANTATION THERAPY USING THE LIVER STEM-LIKE CELLS DIFFERENCIATED BY CELL BIOTHECNOLOGY

细胞生物技术分化的肝干细胞肝细胞移植治疗的进展

• 批准号: 11557091
• 负责人: KOGURE Kimitaka
• 金额: $ 8.58万
• 依托单位: Gunma University Faculty of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557091/
• 关键词: liver stem-like cell; hepatocyte transplantation; artificial liver; TGF-β; activin A; gene transfer; dominant negative receptor of TGF-β and activin A; adenovirus vector; 人工肝; 肝細胞培養; 肝再生; アクチビン; フォリスタチン

Augmentation of liver regeneration, with an artificial support to maintain liver function necessary for survival, would be beneficial for the treatment of fulminant hepatic failure caused by viral infection and hepatic toxins. As well, massive hepatectomy in the treatment of hepatocellular carcinoma can be performed safely if the function of the remnant liver is effectively supported by the alternative livers. The present study was conducted to address this issue. For this purpose, we intended to develop the hepatocyte transplantation therapy from many types of the alternative livers. We completed the technology of efficiently extracting a stem-like liver cells from rat liver. The stem-like liver cells was proliferated and transplanted into the body of the rat after the differentiation of these cells. We constructed a few mm x 10 mm size of hepatic mass in the body of the rat by transplantation of the minimal hepatocytes. The hepatic mass showed the lobular structures encircled with th … More e sinusoidal components and survived over 3 months.As a related experiment, we conducted the study to assess the role of transforming growth factor β (TGF-β) and activin(s) in the regulation of the mass of the liver. We eliminated TGF β or activin signaling in intact rat liver by adenovirus-mediated transfer of the gene encoding truncated type II TGF-β receptor (AdextTR) or truncated type II activin receptor (Adext AR). In AdextTR and Adext AR-treated rats, nuclear labeling with BrDU was significantly higher than that in AdextLacZ or saline treated rats. Immunoreactivity of TGF-β and activin A increased in the liver after the blockade of the activin or TGF-β signaling. These results indicate that blockade of the action of either TGF-β or activin leads to the initiation of DNA synthesis in intact liver (Hepatology, 2001 ; 34 : 918-925).Aiming at the completion of the functional artificial hepatic mass in treating the patients of fulminant hepatic failure, the liver stem-like cells obtained from AdextTR and Adext AR-treated rats are cultured and proliferated and then transplanted into the body of the rat. Less

肝脏再生的增强，并提供人工支持以维持生存所必需的肝功能，将有益于治疗由病毒感染和肝毒素引起的暴发性肝衰竭。同样，如果替代生命有效地支持残余肝脏的功能，则可以安全地进行肝细胞癌的大规模肝切开术。本研究是为了解决这个问题。为此，我们打算从许多类型的替代生活中开发肝细胞移植疗法。我们完成了有效从大鼠肝脏中提取茎状肝细胞的技术。分化这些细胞后，将茎状的肝细胞增殖并移植到大鼠体内。我们通过移植最小的肝细胞在大鼠体内构建了几毫米x 10 mm的肝质量。肝细胞表明，卵形结构包围着……更多的正弦曲线成分并存活了3个月。作为一项相关实验，我们进行了研究，以评估转化生长因子β（TGF-β）和激活素在肝脏质量调节中的作用。我们通过腺病毒介导的编码截短的II型TGF-β受体（ADEXTTR）或II型II型激活素受体（Adext AR）的基因转移来消除完整大鼠肝脏中TGFβ或激活素信号传导。 Adexttr和Adext AR处理的大鼠，用BRDU核标记明显高于Adextlacz或盐水处理的大鼠。阻断激活素或TGF-β信号传导后，TGF-β和激活素A的免疫反应性增加。这些结果表明，TGF-β或活化蛋白的作用阻塞导致完整肝脏中DNA合成的倡议（Hepatology，2001; 34：918-925）。在功能性人工肝质量完成时，在处理功能性人工肝质量时会在治疗抗乳酸型的患者中，并在治疗均具有抗乳液的病人中，并具有适应性的细胞，并具有适应性的细胞，并具有适应性的hepatitic sikext and cornext and corneft and cornext and cornext and corneft and coreft and corneft and corneft and cornext and cornext and corneft and corneft and corneft and。并扩散，然后移植到大鼠的身体中。较少的

项目成果

Kimitaka Kogure: "A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized rats"Gastroenterology. 108. 1136-1142 (1995)

Kimitaka Kogure：“单次门静脉注射卵泡抑素可加速部分肝切除大鼠的肝脏再生”胃肠病学。

Kimitaka Kogure: "ntrafenous administration of Follistatin:;Delivery to the liver and effect of liver rgeneration after partial hepatectomy"Hepatology. 242. 361-366 (1996)

Kimitaka Kogure：“静脉注射卵泡抑素：；部分肝切除术后肝脏的输送和肝脏再生的影响”肝病学。

Kimitaka Kogure: "Immediate onset of DNA synthesis induced by intraportally administrated follistain in 90% hepatectomized rats"Abstract(37th World Congress of International Society of Surgery). 6. (1997)

Kimitaka%20Kogure:%20“立即%20onset%20of%20DNA%20synthesis%20induced%20by%20intraportally%20administated%20follistin%20in%2090%%20hepatectomized%20rats”摘要(37th%20World%20Congress%20of%20International%20Society%

Takeshi Ichikawa: "Transforming growth factor beta and activin tonically inhibit DNA synthesis in the rat liver"Hepatology. 34(5). 918-925 (2001)

Takeshi Ichikawa：“转化生长因子 β 和激活素强效抑制大鼠肝脏中的 DNA 合成”肝病学。

Kimitaka Kogure: "Intrafenous administration of Follistatin;Delivery to the liver and effect of liver rgeneration"Abstract(10th International Congress of Endocrinology). 825-825 (1996)

Kimitaka Kogure：“静脉注射卵泡抑素；递送至肝脏和肝脏再生的效果”摘要（第十届国际内分泌学大会）。