Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/Enhancer-binding protein β
Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/Enhancer-binding protein β
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DOI：
10.1002/hep.21766
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发表时间：
2007-09-01
期刊：
影响因子：
13.5
通讯作者：
Ferberl, Sarah
中科院分区：
文献类型：
--
作者：
Meivar-Levy, Irit;Sapir, Tamar;Ferberl, Sarah
人们认为，由于缺乏有效的去分化途径，哺乳动物的成体组织缺乏承担新的发育命运所需的可塑性。然而，转录因子胰腺和十二指肠同源盒基因1(PDX-1)在肝脏异位表达后激活胰腺谱系发育和胰岛素产生的能力已得到充分证实，这表明成年肝细胞具有令人惊讶的剩余可塑性。本研究试图从机制上解释PDX-1赋予肝细胞胰腺特性和功能的能力。我们证明，PDX-1在正常的胰腺器官发生和胰岛β细胞功能中发挥重要作用，并具有激活肝脏中多个胰腺标志物的潜力，也可以指导肝脏去分化。PDX-1抑制成人肝脏的基因表达，并激活未成熟的肝脏标志物甲胎蛋白的表达。我们提出的证据表明，PDX-1通过抑制关键的肝脏转录因子CCAAT/增强结合蛋白β而触发肝脏去分化。肝脏去分化对于肝脏中成熟的胰腺功能的激活是必要的，但不是充分的。结论：我们的研究提示PDX-1在肝脏中具有双重作用。诱导肝脏去分化，激活胰腺血统。对去分化信号的识别可以提高赋予哺乳动物成熟组织可塑性的能力，以获得在再生医学领域实现的新的发育命运和功能。
It is believed that adult tissues in mammals lack the plasticity needed to assume new developmental fates because of the absence of efficient pathways of dedifferentiation. However, the well-documented ability of the transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) to activate pancreatic lineage development and insulin production following ectopic expression in liver suggests a surprising degree of residual plasticity in adult liver cells. This study seeks a mechanistic explanation for the capacity of PDX-1 to endow liver cells with pancreatic characteristics and function. We demonstrate that PDX-1, previously shown to play an essential role in normal pancreatic organogenesis and pancreatic beta-cell function and to possess the potential to activate multiple pancreatic markers in liver, can also direct hepatic dedifferentiation. PDX-1 represses the adult hepatic repertoire of gene expression and activates the expression of the immature hepatic marker alpha-fetoprotein. We present evidence indicating that PDX-1 triggers hepatic dedifferentiation by repressing the key hepatic transcription factor CCAAT/enhancerbinding protein beta. Hepatic dedifferentiation is necessary though not sufficient for the activation of the mature pancreatic repertoire in liver. Conclusion: Our study suggests a dual role for PDX-1 in liver. inducing hepatic dedifferentiation and activating the pancreatic lineage. The identification of dedifferentiation signals may promote the capacity to endow mature tissues in mammals with the plasticity needed for acquiring novel developmental fates and functions to be implemented in the field of regenerative medicine.