Generation of functional hepatocytes from human spermatogonial stem cells.
Generation of functional hepatocytes from human spermatogonial stem cells.
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DOI：
10.18632/oncotarget.7092
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发表时间：
2016-02-23
期刊：
影响因子：
--
通讯作者：
He Z
中科院分区：
文献类型：
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作者：
Chen Z;Sun M;Yuan Q;Niu M;Yao C;Hou J;Wang H;Wen L;Liu Y;Li Z;He Z
从干细胞和/或肝外组织中生成功能性人肝细胞可以为治疗肝脏疾病提供重要的细胞来源。精原干细胞（SSCs）具有无限的可塑性，可以去分化和转分化到其他细胞系。然而，尚未实现从人ssc中生成成熟和功能的肝细胞。在这里，我们首次报道了通过三步诱导，使用确定的条件培养基将人ssc直接转分化为成熟和功能的肝细胞。人类ssc首先被转分化为肝干细胞，其形态学和生物潜能特性证明了其共同表达肝细胞和胆管细胞标记，但不是胚胎干细胞的标志。进一步诱导肝干细胞分化为成熟肝细胞，通过其形态特征和强烈表达CK8、CK18、ALB、AAT、TF、TAT和细胞色素酶而不是CK7或CK19来鉴定。值得注意的是，来源于人ssc的成熟肝细胞具有人肝细胞的功能属性，因为它们可以产生白蛋白，去除氨，摄取和释放吲哚菁绿。此外，在人ssc向成熟肝细胞的转分化过程中，β-CATENIN、HNF4A、FOXA1和GATA4的表达上调。总的来说，人ssc可以直接转分化为成熟的功能性肝细胞。这项研究可以为肝脏疾病的治疗和药物毒理学筛选提供宝贵的人类肝细胞来源，并为人类肝脏再生的机制提供新的见解。
To generate functional human hepatocytes from stem cells and/or extra-hepatic tissues could provide an important source of cells for treating liver diseases. Spermatogonial stem cells (SSCs) have an unlimited plasticity since they can dedifferentiate and transdifferentiate to other cell lineages. However, generation of mature and functional hepatocytes from human SSCs has not yet been achieved. Here we have for the first time reported direct transdifferentiation of human SSCs to mature and functional hepatocytes by three-step induction using the defined condition medium. Human SSCs were first transdifferentiated to hepatic stem cells, as evidenced by their morphology and biopotential nature of co-expressing hepatocyte and cholangiocyte markers but not hallmarks for embryonic stem cells. Hepatic stem cells were further induced to differentiate into mature hepatocytes identified by their morphological traits and strong expression of CK8, CK18, ALB, AAT, TF, TAT, and cytochrome enzymes rather than CK7 or CK19. Significantly, mature hepatocytes derived from human SSCs assumed functional attributes of human hepatocytes, because they could produce albumin, remove ammonia, and uptake and release indocyanine green. Moreover, expression of β-CATENIN, HNF4A, FOXA1 and GATA4 was upregulated during the transdifferentiation of human SSCs to mature hepatocytes. Collectively, human SSCs could directly transdifferentiate to mature and functional hepatocytes. This study could offer an invaluable source of human hepatocytes for curing liver disorders and drug toxicology screening and provide novel insights into mechanisms underlying human liver regeneration.