Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.
Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.
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DOI：
10.1038/nbt.3275
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发表时间：
2015-08
影响因子：
46.9
通讯作者：
Vallier L
中科院分区：
文献类型：
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作者：
Sampaziotis F;de Brito MC;Madrigal P;Bertero A;Saeb-Parsy K;Soares FAC;Schrumpf E;Melum E;Karlsen TH;Bradley JA;Gelson WT;Davies S;Baker A;Kaser A;Alexander GJ;Hannan NRF;Vallier L
胆道疾病的研究一直受到缺乏原代人胆管细胞的限制。在这里，我们提出了一个有效的，无血清的协议，为人类诱导多能干细胞定向分化成胆管细胞样细胞（CLC）。CLC具有胆管细胞的功能特征，包括胆汁酸转运、碱性磷酸酶活性、γ-谷氨酰转肽酶活性以及对促胰液素、生长抑素和VEGF的生理反应。我们使用CLC在体外模拟Alagille综合征、多囊肝病和囊性纤维化（CF）相关胆管病的关键特征。此外，我们使用从健康个体和患有多囊肝病的患者产生的CLC来再现药物维拉帕米和奥曲肽的作用，并且我们表明实验性CF药物VX 809在体外挽救CF胆管病的疾病表型。我们的分化方案将促进控制胆道发展的生物学机制的研究，以及疾病建模和药物筛选。
The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, gamma-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and VEGF. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development as well as disease modeling and drug screening.