Schmelzer Eva, Zhang Lili, Bruce Andrew, Wauthier Eliane, Ludlow John, Yao Hsin-lei, Moss Nicholas, Melhem Alaa, McClelland Randall, Turner William, Kulik Michael, Sherwood Sonya, Tallheden Tommi, Cheng Nancy, Furth Mark E, Reid Lola M
Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
J Exp Med. 2007 Aug 6;204(8):1973-87. doi: 10.1084/jem.20061603. Epub 2007 Jul 30.
Human hepatic stem cells (hHpSCs), which are pluripotent precursors of hepatoblasts and thence of hepatocytic and biliary epithelia, are located in ductal plates in fetal livers and in Canals of Hering in adult livers. They can be isolated by immunoselection for epithelial cell adhesion molecule-positive (EpCAM+) cells, and they constitute approximately 0.5-2.5% of liver parenchyma of all donor ages. The self-renewal capacity of hHpSCs is indicated by phenotypic stability after expansion for >150 population doublings in a serum-free, defined medium and with a doubling time of approximately 36 h. Survival and proliferation of hHpSCs require paracrine signaling by hepatic stellate cells and/or angioblasts that coisolate with them. The hHpSCs are approximately 9 microm in diameter, express cytokeratins 8, 18, and 19, CD133/1, telomerase, CD44H, claudin 3, and albumin (weakly). They are negative for alpha-fetoprotein (AFP), intercellular adhesion molecule (ICAM) 1, and for markers of adult liver cells (cytochrome P450s), hemopoietic cells (CD45), and mesenchymal cells (vascular endothelial growth factor receptor and desmin). If transferred to STO feeders, hHpSCs give rise to hepatoblasts, which are recognizable by cordlike colony morphology and up-regulation of AFP, P4503A7, and ICAM1. Transplantation of freshly isolated EpCAM+ cells or of hHpSCs expanded in culture into NOD/SCID mice results in mature liver tissue expressing human-specific proteins. The hHpSCs are candidates for liver cell therapies.
人肝干细胞（hHpSCs）是成肝细胞的多能前体细胞，进而也是肝细胞和胆管上皮细胞的前体细胞，位于胎儿肝脏的导管板和成人肝脏的赫林管中。它们可通过免疫筛选上皮细胞黏附分子阳性（EpCAM+）细胞来分离，在所有供体年龄的肝实质中约占0.5 - 2.5%。hHpSCs的自我更新能力表现为在无血清、特定培养基中扩增超过150个群体倍增后表型稳定，倍增时间约为36小时。hHpSCs的存活和增殖需要与它们共同分离的肝星状细胞和/或成血管细胞的旁分泌信号。hHpSCs直径约为9微米，表达细胞角蛋白8、18和19、CD133/1、端粒酶、CD44H、claudin 3和白蛋白（弱阳性）。它们对甲胎蛋白（AFP）、细胞间黏附分子（ICAM）1以及成人肝细胞标志物（细胞色素P450）、造血细胞标志物（CD45）和间充质细胞标志物（血管内皮生长因子受体和结蛋白）呈阴性。如果转移到STO饲养层细胞上，hHpSCs会产生成肝细胞，可通过索状集落形态以及AFP、P4503A7和ICAM1的上调来识别。将新鲜分离的EpCAM+细胞或培养扩增的hHpSCs移植到NOD/SCID小鼠体内会产生表达人类特异性蛋白质的成熟肝组织。hHpSCs是肝细胞治疗的候选细胞。
