Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes.
Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes.
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DOI：
10.1016/j.stemcr.2015.04.017
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发表时间：
2015-07-14
影响因子：
5.9
通讯作者：
Roy-Chowdhury N
中科院分区：
文献类型：
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作者：
Chen Y;Li Y;Wang X;Zhang W;Sauer V;Chang CJ;Han B;Tchaikovskaya T;Avsar Y;Tafaleng E;Madhusudana Girija S;Tar K;Polgar Z;Strom S;Bouhassira EE;Guha C;Fox IJ;Roy-Chowdhury J;Roy-Chowdhury N
肝细胞移植具有治愈遗传性肝病的潜力，但其应用受到供体肝脏稀缺的阻碍。因此，我们探讨了从人诱导多能干细胞（iPSC）分化的肝细胞样细胞（iHep）移植是否可以改善遗传性肝病。将从人皮肤成纤维细胞重编程的iPSC分化为iHep，将其移植到尿苷二磷酸葡萄糖醛酸葡萄糖醛酸转移酶-1（UGT 1A 1）缺陷型古恩大鼠的肝脏中，Gunn大鼠是Crigler-Najjar综合征1（CN 1）的模型，其中升高的未结合胆红素导致脑损伤和死亡。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，UGT 1A 1 + iHep簇占预处理肝叶的2.5%-7.5%。血清胆红素下降30%-60%，胆汁排泄胆红素葡萄糖醛酸苷，表明移植的iHep表达UGT 1A 1活性，肝细胞的出生后功能。因此，iHeps值得进一步探索作为治疗遗传性肝病的肝细胞的可再生来源。人皮肤成纤维细胞衍生的iPSC分化为肝细胞样iHep将iHep移植到古恩大鼠（Crigler-Najjar综合征模型1）中iHep在古恩大鼠肝脏中的移植降低了血清胆红素水平iHep可能在治疗肝脏代谢疾病方面有潜在用途Roy-Chowdhury和同事表明，人类iPSC分化为肝细胞样iHep细胞，移植到UGT 1A 1缺陷型古恩大鼠的肝脏中，Crigler-Najjar综合征1的模型，其中高胆红素血症导致脑损伤和死亡。iHep移植后，血清胆红素下降30%~ 60%，胆汁中出现胆红素葡萄糖醛酸苷，表明移植的iHep表达了UGT 1A 1，这是一种出生后的肝细胞功能。
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. Human skin fibroblast-derived iPSCs were differentiated to hepatocyte-like iHeps iHeps were transplanted into Gunn rats, a model of Crigler-Najjar syndrome 1 Engraftment of the iHeps in Gunn rat livers reduced serum bilirubin levels iHeps may be potentially useful in treating liver-based metabolic disorders Roy-Chowdhury and colleagues show that human iPSCs differentiated to hepatocyte-like iHep cells engraft into the liver of UGT1A1-deficient Gunn rats, a model of Crigler-Najjar syndrome 1, where hyperbilirubinemia causes brain injury and death. After iHep transplantation, serum bilirubin declined by 30%–60% and bilirubin glucuronides appeared in bile, indicating that the engrafted iHeps expressed UGT1A1, a postnatal hepatocyte function.