Department of Cell and Molecular Physiology, Biomedical Engineering, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC 27599, USA.
Hepatology. 2011 Dec;54(6):2159-72. doi: 10.1002/hep.24590.
Multipotent stem/progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato-pancreatic common duct, cystic duct, and hilum. They express endodermal transcription factors (e.g., Sox9, SOX17, FOXA2, PDX1, HES1, NGN3, PROX1) intranuclearly, stem/progenitor surface markers (EpCAM, NCAM, CD133, CXCR4), and sometimes weakly adult liver, bile duct, and pancreatic genes (albumin, cystic fibrosis transmembrane conductance regulator [CFTR], and insulin). They clonogenically expand on plastic and in serum-free medium, tailored for endodermal progenitors, remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ≈36 hours and slowing to one every 2-3 days. Transfer into distinct culture conditions, each comprised of a specific mix of hormones and matrix components, yields either cords of hepatocytes (express albumin, CYP3A4, and transferrin), branching ducts of cholangiocytes (expressing anion exchanger-2-AE2 and CFTR), or regulatable C-peptide secreting neoislet-like clusters (expressing glucagon, insulin) and accompanied by changes in gene expression correlating with the adult fate. Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes, whereas if into fat pads of streptozocin-induced diabetic mice, results in functional islets secreting glucose-regulatable human C-peptide.
The phenotypes and availability from all age donors suggest that these stem/progenitors have considerable potential for regenerative therapies of liver, bile duct, and pancreatic diseases including diabetes.
从所有年龄段的人肝外胆管的胆小管周围腺中可以发现多能干细胞/祖细胞，且在肝胰共同管、胆囊管和门脉中数量很多。它们在核内表达内胚层转录因子（例如 Sox9、SOX17、FOXA2、PDX1、HES1、NGN3、PROX1）、干细胞/祖细胞表面标志物（EpCAM、NCAM、CD133、CXCR4），有时还弱表达成人肝、胆管和胰腺基因（白蛋白、囊性纤维化跨膜电导调节因子[CFTR]和胰岛素）。它们在塑料和无血清培养基中克隆扩增，针对内胚层祖细胞进行了优化，在数月内保持未分化细胞的表型稳定，细胞分裂最初约每 36 小时一次，然后减缓至每 2-3 天一次。转移到不同的培养条件下，每种条件都由特定的激素和基质成分混合而成，分别产生表达白蛋白、CYP3A4 和转铁蛋白的肝细胞索、表达阴离子交换器-2-AE2 和 CFTR 的胆管分支，或可调节的 C 肽分泌的类胰岛样簇（表达胰高血糖素、胰岛素），并伴有与成人命运相关的基因表达变化。将其移植到免疫功能低下的小鼠静止肝脏中可产生有功能的人肝细胞和胆管细胞，而如果移植到链脲佐菌素诱导的糖尿病小鼠的脂肪垫中，则可产生可调节葡萄糖分泌的有功能的人 C 肽分泌胰岛。
这些表型和来自所有年龄段供体的可用性表明，这些干细胞/祖细胞具有治疗肝脏、胆管和胰腺疾病（包括糖尿病）的再生疗法的巨大潜力。
