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

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费用高昂的限制。同种异体肝细胞移植已被研究作为肝移植的替代方法。近年来的研究表明，骨髓细胞在体内外均可分化为脂肪细胞、心肌细胞、皮肤上皮细胞、神经细胞、肝细胞等多种细胞系。此外，Lagasse，et.等人发现骨髓细胞移植到富马酰乙酰乙酸水解酶（FAH）缺陷型小鼠中，人致命先天性酪氨酸血症类型的动物模型拯救了小鼠并恢复了它们的肝功能，以及Li，et. Al.的研究显示，颈动脉内给予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 关于我们 研究表明，骨髓细胞是细胞移植治疗的理想资源。<2003>我们研究了通过异基因骨髓细胞移植纠正长濑无白蛋白血症大鼠（NAR）先天性白蛋白缺乏的可行性。7周龄雄性NAR用作受体，6- 8周龄雄性Sprague-Dawley（SD）大鼠用作同种异体移植供体。NAR被分为三组：骨髓移植（BMT）组（n=10），其中骨髓细胞被输注到肝脏中;肝细胞移植（HCT）组（n=8），其中肝细胞被移植到肝脏中;以及对照组（n=8），其中PBS被注射到门静脉中。血清白蛋白水平作为移植细胞功能的指标进行测量，并与免疫组化和免疫荧光技术评估受体肝脏中移植细胞的表型特征。细胞移植后8周，BMT组和HCT组的血清白蛋白水平显著高于对照组。骨髓来源的肝细胞样细胞在NAR的肝脏中表达白蛋白。根据该结果，骨髓细胞可以在体内分化为肝细胞样细胞。结果表明，骨髓细胞移植是一种有效的治疗先天性无白蛋白血症的大鼠模型，并建议异基因骨髓细胞移植可作为一种有效的治疗遗传代谢性疾病。<2004>最近的研究表明，链脲佐菌素诱导的糖尿病后骨髓细胞移植可以支持胰腺β细胞群的恢复和部分逆转高血糖。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水平维持在高值。BMT组胰腺导管细胞中c-Met表达频率及其增殖活性和分化反应均高于PBS处理组，导致内源性胰岛素产生细胞数量增加。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少

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