Experimental conversion of liver to pancreas
Experimental conversion of liver to pancreas
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DOI：
10.1016/s0960-9822(02)01434-3
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发表时间：
2003-01-21
期刊：
影响因子：
9.2
通讯作者：
Slack, JMW
中科院分区：
文献类型：
--
作者：
Horb, ME;Shen, CN;Slack, JMW
背景：肝脏和胰腺在胚胎发育中起源于相邻的内胚层区域。Pdx 1是一种关键的转录因子，对胰腺的发育至关重要，但在肝脏中不表达。本研究的目的是确定是否基于Pdx 1的基因过表达协议将能够导致转换的肝脏pancreat.Results：我们表明，一个修改后的形式的Pdx 1，携带的VP 16转录激活域，可以导致转换的肝脏胰腺，在体内和体外。制备携带构建体TTR-Xlhbox 8-VP 16：Elas-GFP的转基因非洲爪蟾蝌蚪。Xlhbox 8是Pdx 1的爪蟾同源物，TTR（转甲状腺素蛋白）启动子指导表达至肝脏，GFP在弹性蛋白酶启动子的控制下，并提供胰腺分化的实时可见标记。在转基因蝌蚪中，部分或全部肝脏转化为胰腺，包含外分泌和内分泌细胞，而肝脏分化产物从转化为胰腺的区域丢失。事件的时间安排使得肝脏在Xlhbox 8-VP 16表达时正在分化，因此我们认为这是转分化事件而不是胚胎发育的重编程。此外，这同样的结构将带来转分化的人肝细胞在文化中，形成外分泌和内分泌celles.Conclusions：我们认为，转换的肝脏胰腺可能是一种新型的治疗胰岛素依赖型糖尿病的基础。虽然转基因的表达是短暂的，一旦异位胰腺建立，它就持续存在。
Background: The liver and the pancreas arise from adjacent regions of endoderm in embryonic development. Pdx1 is a key transcription factor that is essential for the development of the pancreas and is not expressed in the liver. The aim of this study was to determine whether a gene overexpression protocol based on Pdx1 would be able to cause conversion of liver to pancreas.Results: We show that a modified form of Pdx1, carrying the VP16 transcriptional activation domain, can cause conversion of liver to pancreas, both in vivo and in vitro. Transgenic Xenopus tadpoles carrying the construct TTR-Xlhbox8-VP16:Elas-GFP were prepared. Xlhbox8 is the Xenopus homolog of Pdx1, the TTR (transthyretin) promoter directs expression to the liver, and the GFP is under the control of an elastase promoter and provides a real-time visible marker of pancreatic differentiation. In the transgenic tadpoles, part or all of the liver is converted to pancreas, containing both exocrine and endocrine cells, while liver differentiation products are lost from the regions converted to pancreas. The timing of events is such that the liver is differentiating by the time Xlhbox8-VP16 is expressed, so we consider this a transdifferentiation event rather than a reprogramming of embryonic development. Furthermore, this same construct will bring about transdifferentiation of human hepatocytes in culture, with formation of both exocrine and endocrine cells.Conclusions: We consider that the conversion of liver to pancreas could be the basis of a new type of therapy for insulin-dependent diabetes. Although expression of the transgene is transient, once the ectopic pancreas is established, it persists thereafter.