Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Radiation Oncology and Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Stem Cell Reports. 2015 Jul 14;5(1):22-30. doi: 10.1016/j.stemcr.2015.04.017. Epub 2015 Jun 11.
Hepatocyte transplantation has the potential to cure inherited liver diseases, but its application is impeded by a scarcity of donor livers. Therefore, we explored whether transplantation of hepatocyte-like cells (iHeps) differentiated from human induced pluripotent stem cells (iPSCs) could ameliorate inherited liver diseases. iPSCs reprogrammed from human skin fibroblasts were differentiated to iHeps, which were transplanted into livers of uridinediphosphoglucuronate glucuronosyltransferase-1 (UGT1A1)-deficient Gunn rats, a model of Crigler-Najjar syndrome 1 (CN1), where elevated unconjugated bilirubin causes brain injury and death. To promote iHep proliferation, 30% of the recipient liver was X-irradiated before transplantation, and hepatocyte growth factor was expressed. After transplantation, UGT1A1+ iHep clusters constituted 2.5%-7.5% of the preconditioned liver lobe. A decline of serum bilirubin by 30%-60% and biliary excretion of bilirubin glucuronides indicated that transplanted iHeps expressed UGT1A1 activity, a postnatal function of hepatocytes. Therefore, iHeps warrant further exploration as a renewable source of hepatocytes for treating inherited liver diseases.
肝细胞移植具有治愈遗传性肝脏疾病的潜力，但由于供体肝脏短缺，其应用受到阻碍。因此，我们探讨了是否可以通过移植人诱导多能干细胞（iPSC）分化而来的肝样细胞（iHeps）来改善遗传性肝脏疾病。我们将人皮肤成纤维细胞重编程为 iPSC，然后将其分化为 iHeps，将其移植到 UGT1A1 缺陷型 Gunn 大鼠（CN1 型先天性非溶血性高胆红素血症 1 型的模型）的肝脏中，该模型由于未结合胆红素升高而导致脑损伤和死亡。为了促进 iHep 增殖，在移植前对 30%的受体肝脏进行 X 射线照射，并表达肝细胞生长因子。移植后，UGT1A1+iHep 簇构成预处理肝叶的 2.5%-7.5%。血清胆红素下降 30%-60%和胆红素葡萄糖醛酸苷的胆汁排泄表明，移植的 iHeps 表达了 UGT1A1 活性，这是肝细胞的一种出生后功能。因此，iHeps 作为治疗遗传性肝脏疾病的可再生肝细胞来源值得进一步探索。
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