Hedgehog regulates yes-associated protein 1 in regenerating mouse liver.
Hedgehog regulates yes-associated protein 1 in regenerating mouse liver.
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DOI：
10.1002/hep.28542
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Diehl AM
中科院分区：
文献类型：
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作者：
Swiderska-Syn M;Xie G;Michelotti GA;Jewell ML;Premont RT;Syn WK;Diehl AM
成人肝脏再生需要诱导和抑制多种类型肝细胞的增殖活性。单个肝细胞内增殖活性改变所需的基因表达全局变化的协调机制，以及不同类型肝细胞间增殖活性的协调机制，目前尚不清楚。在胎儿发育过程中活跃的形态发生信号通路，包括Hedgehog和Hippo/ yes相关蛋白1 (Yap1)，调节成年期肝脏再生。当这些通路失调时，肝硬化和肝癌就会发生，但在有效的肝脏再生过程中，对协调和控制形态发生信号的机制知之甚少。我们通过研究完整小鼠和培养的肝细胞，评估了Hedgehog通路在肝脏再生过程中控制Yap1激活的假设。在培养的肝星状细胞（HSC）中，破坏Hedgehog信号阻断了Yap1的激活，而敲低Yap1则抑制了Yap1和Hedgehog调控基因的诱导，这些基因使HSC成为肌成纤维细胞（MF）。在小鼠实验中，破坏MF中的Hedgehog信号通路会抑制ph后的肝脏再生。肝上皮室的增殖活性降低是由于肝细胞中基质来源的激活Yap1和Hedgehog通路的旁分泌信号缺失所致。这阻止了肝细胞上调Yap1和刺猬调节的转录因子，而这些转录因子通常会促进肝细胞的增殖。在部分肝切除术后，HSC中的形态发生信号对于肝细胞重编程以再生肝上皮室是必要的。这一发现确定了可能靶向纠正肝硬化和肝癌修复缺陷的新分子。
Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSC), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1 and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MF). In mice, disrupting Hedgehog signaling in MF inhibited liver regeneration after PH. Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up-regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation. Morphogenic signaling in HSC is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment after partial hepatectomy. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer.