Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers
Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers
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DOI：
10.1136/gut.2005.090050
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发表时间：
2007-03-01
期刊：
影响因子：
24.5
通讯作者：
Christ, Bruno
中科院分区：
文献类型：
--
作者：
Aurich, Ines;Mueller, Lutz P.;Christ, Bruno
目的：目前，肝细胞移植作为全肝移植替代品的临床成功受到用于分离可移植肝细胞的合适供体器官的限制。因此，需要新的细胞来源来提供足够质量的肝细胞用于临床。人骨髓间充质干细胞（MSCs）在体内和体外都有可能分化为肝细胞。方法：采用密度梯度离心和塑料贴壁法分离MSCs，在人肝细胞生长培养基中分化，移植于免疫缺陷Pfp/Rag2小鼠。结果：在这里，我们证明了人间充质干细胞在体外获得肝细胞的特征形态和功能，以响应特定的生长因子。具体来说，预处理的MSCs储存糖原，合成尿素，并具有活性的肝细胞特异性基因启动子磷酸烯醇丙酮酸羧激酶（PCK1）。在移植到免疫缺陷小鼠的肝脏后，预处理的MSCs主要在肝小叶的门静脉周围部分移植。在原位，细胞继续储存糖原，表达PCK1、connexin32、白蛋白和人肝细胞特异性抗原HepPar1，表明移植细胞在区域整合后保留了肝细胞的突出特性。结论：人骨髓间充质干细胞可作为肝细胞样细胞增殖的新来源，适用于肝脏疾病的细胞治疗。
Aims: At present, clinical success of hepatocyte transplantation as an alternative to whole liver transplantation is hampered by the limited availability of suitable donor organs for the isolation of transplantable hepatocytes. Hence, novel cell sources are required to deliver hepatocytes of adequate quality for clinical use. Mesenchymal stem cells (MSCs) from human bone marrow may have the potential to differentiate into hepatocytes in vitro and in vivo.Methods: Isolated MSCs were selected by density gradient centrifugation and plastic adherence, differentiated in the presence of human hepatocyte growth medium and transplanted in immunodeficient Pfp/Rag2 mice.Results: Here, we demonstrate that human MSCs gain in vitro the characteristic morphology and function of hepatocytes in response to specified growth factors. Specifically, preconditioned MSCs store glycogen, synthesise urea and feature the active hepatocyte-specific gene promoter of phosphoenolpyruvate carboxykinase (PCK1). After transplantation into livers of immunodeficient mice, preconditioned MSCs engraft predominantly in the periportal portion of the liver lobule. In situ, the cells continue to store glycogen and express PCK1, connexin32, albumin and the human hepatocyte-specific antigen HepPar1, indicating that the transplanted cells retain prominent qualities of hepatocytes after their regional integration.Conclusion: MSCs derived from human bone marrow may serve as a novel source for the propagation of hepatocyte-like cells suitable for cell therapy in liver diseases.