Proliferation and differentiation of hepatic stem cell from bone marrow cells and possibility of bone marrow transplantation in genetic hepatic disease

骨髓细胞肝干细胞的增殖分化及遗传性肝病骨髓移植的可能性

• 批准号: 15591362
• 负责人: AOKI Takeshi
• 金额: $ 2.24万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591362/
• 关键词: Bone marrow transplantation; Analbuminemic rat; Hepatocyte Growth Factor; Diabetes; Insulin producing cell; 細胞移植; 骨髄細胞; 肝幹細胞; スナムセル; 肝細胞移植; 骨髄細胞移植

Whole liver or partial liver transplantation is the only effective method of treating end-stage liver disease in humans, but its application is limited by an insufficient number of donor organs and the high cost. Allogeneic hepatocyte transplantation has been studied as an alternative method of liver transplantation. But its use also has been limited by the limited number of donors.Many studies in the past several years have shown that bone marrow cells can differentiate into various cell lineage in vitro and in vivo such as lipocyte, cardiac myoblast, skin epithelium, neuron, and hepatocytes lineage. Moreover, Lagasse, et. al. found that bone marrow cell transplantation into fumarylacetoacetate hydrolase (FAH)-deficient mice, an animal model of human fatal congenital tyrosinemia type rescued the mice and restored their liver function, and Li, et. Al. showed improvement of neurologic recovery in a rat stroke model with intracarotid administration of bone marrow stromal cell[6]. These s … More tudies demonstrated that bone marrow cells are an ideal resource for cell transplantation therapy.<2003>We investigated the feasibility of correcting the congenital absence of albumin in Nagase analbuminemic rats (NAR) by allogeneic bone marrow cell transplantation. Seven week-old male NARs were used as recipients, and 6- to 8- week-old male Sprague-Dawley (SD) rats were used as allograft donors. NARs were divided into three groups: a bone marrow transplantation (BMT) group (n=10) in which bone marrow cells were infused into the liver; a hepatocyte transplantation (HCT) group (n=8) in which hepatocytes were transplanted into the liver; and a control group (n=8) in which PBS was injected into the portal vein. Serum albumin levels were measured as an indicator of the function of the grafted cells, and the phenotypic characteristics of the engrafted cells in the recipient's liver were assessed with immunohistochemical and immunofluorescence techniques. At 8 weeks after cell transplantation the serum albumin levels of the BMT group and HCT group were significantly higher than in the control group. The hepatocyte-like cells derived from bone marrow cells expressed albumin in liver of the NARs. From this result, bone marrow cells can differentiate into hepatocyte-like cells in vivo. The results show that bone marrow cell transplantation is an effective treatment for congenital analbuminemia in a rat model and suggest that allogeneic bone marrow cell transplantation can be used as an efficient therapy for hereditary metabolic diseases.<2004>Recent studies have demonstrated that the transplantation of bone marrow cells following diabetes induced by streptozotocin can support the recovery of pancreatic beta-cell mass and a partial reversal of hyperglycemia. To address this issue, we examined whether the c-Met/hepatocyte growth factor (HGP) signaling pathway was involved in the recovery of beta-cell injury after bone marrow transplantation (BMT). In this model, donor-derived bone marrow cells were positive for HGF immunoreactivity in the recipient spleen, liver, lung, and pancreas as well as in the host hepatocytes. Indeed, plasma HGF levels were maintained at a high value. The frequency of c-Met expression and its proliferative activity and differentiative response in the pancreatic ductal cells in the BMT group were greater than those in the PBS-treated group, resulting in an elevated number of endogenous insulin-producing cells. The induction of the c-Met/HGF signaling pathway following BMT promotes pancreatic regeneration in diabetic rats. Less

全肝或部分肝移植是治疗人类终末期肝病的唯一有效方法，但其应用受到供体器官数量不足和成本高昂的限制。同种异体肝细胞移植作为肝移植的一种替代方法已被研究。但其应用也受到供体数量有限的限制。近年来的许多研究表明，骨髓细胞在体外和体内都可以分化为多种细胞系，如脂肪细胞、心肌成肌细胞、皮肤上皮细胞、神经元和肝细胞系。此外，Lagse等.艾尔发现将骨髓细胞移植到延胡索乙酸酯水解酶(FAH)缺陷的小鼠，建立了人类致死性先天性酪氨酸血症的动物模型，拯救了小鼠，恢复了它们的肝功能，并与Li等人进行了比较。艾尔。结果显示，颈动脉注射骨髓基质细胞可改善大鼠中风模型的神经功能恢复[6]。这些S…更多的研究表明，骨髓细胞是细胞移植治疗的理想来源。我们探讨了异基因骨髓细胞移植纠正NAR大鼠先天性白蛋白缺乏症的可行性。受者为7周龄雄性NAR，供体为6~8周龄雄性SD大鼠。实验分为3组：骨髓移植(BMT)组(n=10)，肝细胞移植(HCT)组(n=8)，PBS门静脉注射对照组(n=8)。测定血清白蛋白水平作为移植细胞功能的指标，并用免疫组织化学和免疫荧光技术评价移植细胞在受体肝脏中的表型特征。细胞移植后8周，BMT组和HCT组的血清白蛋白水平明显高于对照组。从骨髓来源的肝细胞样细胞在NAR的肝脏表达白蛋白。根据这一结果，骨髓细胞可以在体内分化为肝细胞样细胞。结果表明，骨髓细胞移植是治疗大鼠先天性蛋白血症的有效方法，提示异基因骨髓细胞移植可作为遗传性代谢性疾病的有效治疗方法。最近的研究表明，链脲佐菌素诱导的糖尿病后的骨髓细胞移植可以支持胰岛β细胞量的恢复和高血糖的部分逆转。为了解决这个问题，我们研究了c-Met/肝细胞生长因子(HGP)信号通路是否参与了骨髓移植(BMT)后β细胞损伤的恢复。在该模型中，供体来源的骨髓细胞在受体的脾、肝、肺和胰腺以及宿主肝细胞中呈HGF免疫反应阳性。事实上，血浆HGF水平维持在较高水平。BMT组大鼠胰腺导管细胞c-Met表达频率及其增殖活性和分化反应均高于PBS组，导致内源性胰岛素分泌细胞数量增加。骨髓移植后c-Met/HGF信号通路的诱导促进糖尿病大鼠胰腺再生。较少

项目成果

Elevation of serum albumin levels in Nagase Analbuminemic Rats by allogeneic bone marrow cell transplantation

同种异体骨髓细胞移植提高长濑无白蛋白血症大鼠血清白蛋白水平

• 发表时间: 2005
• 期刊: European Surgical Research 37
• 作者: Hua L

Hepatoqyte growth factor is constitutively produced by donordehved bone marrow cells and promotes regeneration of pancreatic beta-cells

肝细胞生长因子由供体骨髓细胞组成型产生，促进胰腺 β 细胞的再生

• 发表时间: 2005
• 期刊: Biochemical and Biophysical Research Commuunication 333
• 作者: Hua L;Izumida Y
• 通讯作者: Izumida Y

Hepatocyte growth factor is constitutively produced by donor-derived bone marrow cells and promotes regeneration of pancreatic beta-cells.

• 发表时间: 2005
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Y. Izumida;Takeshi Aoki;D. Yasuda;T. Koizumi;C. Suganuma;Koji Saito;N. Murai;Yoshinori Shimizu;Ken Hayashi;Masanori Odaira;Tomakazu Kusano;M. Kushima;Mitsuo Kudano