Expression of hepatocytic- and biliary-specific transcription factors in regenerating bile ducts during hepatocyte-to-biliary epithelial cell transdifferentiation.
Expression of hepatocytic- and biliary-specific transcription factors in regenerating bile ducts during hepatocyte-to-biliary epithelial cell transdifferentiation.
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DOI：
10.1186/1476-5926-9-9
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发表时间：
2010-12-02
期刊：
影响因子：
--
通讯作者：
Michalopoulos GK
中科院分区：
文献类型：
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作者：
Limaye PB;Bowen WC;Orr A;Apte UM;Michalopoulos GK
在受损的胆汁再生下，先前在大鼠中观察到肝细胞转分化为胆管上皮细胞（BEC），暴露于BEC特异性毒物亚甲基二苯胺（DAPM）后进行胆管结扎（BDL），以及慢性胆汁性肝病患者。然而，促进这种转分化的机制尚未完全了解。在本研究中，收购胆汁特异性转录因子的肝细胞，导致BEC特异性细胞的重新编程的研究作为一个潜在的转分化机制，在两个不同的模型受损的大鼠胆道再生。除了先前检查的DAPM + BDL模型之外，通过重复施用DAPM建立类似慢性胆道损伤的实验模型。使用通常仅在肝细胞中携带DPPIV的二肽基二肽酶IV（DDPIV）嵌合大鼠追踪肝细胞向BEC的转分化。在DAPM处理后，约20%的BEC群体变为DPPIV阳性，表明它们来源于DPPIV阳性肝细胞。DAPM + BDL和重复DAPM暴露后出现的新小管表达肝细胞相关转录因子肝细胞核因子（HNF）4α和胆汁特异性转录因子HNF 1 β。此外，门静脉周围肝细胞表达胆汁标记物CK19，表明门静脉周围肝细胞是转分化细胞的潜在来源。虽然TGFβ1被诱导，但门静脉周围HNF 6的表达并没有显著减少，正如在胚胎胆管发育过程中观察到的那样。综上所述，这些发现表明肝细胞逐渐丧失HNF 4 α和获得HNF 1 β，以及门静脉周围区域TGFβ1表达增加，似乎是肝细胞向BEC转分化的潜在机制。
Under compromised biliary regeneration, transdifferentiation of hepatocytes into biliary epithelial cells (BEC) has been previously observed in rats, upon exposure to BEC-specific toxicant methylene dianiline (DAPM) followed by bile duct ligation (BDL), and in patients with chronic biliary liver disease. However, mechanisms promoting such transdifferentiation are not fully understood. In the present study, acquisition of biliary specific transcription factors by hepatocytes leading to reprogramming of BEC-specific cellular profile was investigated as a potential mechanism of transdifferentiation in two different models of compromised biliary regeneration in rats. In addition to previously examined DAPM + BDL model, an experimental model resembling chronic biliary damage was established by repeated administration of DAPM. Hepatocyte to BEC transdifferentiation was tracked using dipetidyl dipeptidase IV (DDPIV) chimeric rats that normally carry DPPIV only in hepatocytes. Following DAPM treatment, ~20% BEC population turned DPPIV-positive, indicating that they are derived from DPPIV-positive hepatocytes. New ductules emerging after DAPM + BDL and repeated DAPM exposure expressed hepatocyte-associated transcription factor hepatocyte nuclear factor (HNF) 4α and biliary specific transcription factor HNF1β. In addition, periportal hepatocytes expressed biliary marker CK19 suggesting periportal hepatocytes as a potential source of transdifferentiating cells. Although TGFβ1 was induced, there was no considerable reduction in periportal HNF6 expression, as observed during embryonic biliary development. Taken together, these findings indicate that gradual loss of HNF4α and acquisition of HNF1β by hepatocytes, as well as increase in TGFβ1 expression in periportal region, appear to be the underlying mechanisms of hepatocyte-to-BEC transdifferentiation.