Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8.
Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8.
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Hdac1 通过 Sox9b 和 Cdk8 调节双能肝祖细胞再生过程中的分化
DOI：
10.1053/j.gastro.2018.09.039
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发表时间：
2019-01
期刊：
影响因子：
29.4
通讯作者：
Shin D
中科院分区：
文献类型：
--
作者：
Ko S;Russell JO;Tian J;Gao C;Kobayashi M;Feng R;Yuan X;Shao C;Ding H;Poddar M;Singh S;Locker J;Weng HL;Monga SP;Shin D
当肝损伤导致肝细胞增殖受损时，源自胆管上皮细胞 (BEC) 的肝祖细胞 (LPC) 会分化为肝细胞。关于 LPC 分化的机制知之甚少。我们使用斑马鱼和小鼠肝损伤模型来研究其机制。我们使用转基因斑马鱼 Tg(fabp10a:CFP-NTR) 来研究改变表观遗传因子的化合物对 BEC 介导的肝再生的影响。我们分析了组蛋白脱乙酰酶 1 基因 (hdac1) 遭到破坏或暴露于 MS-275（Hdac1、Hdac2 和 Hdac3 的抑制剂）的斑马鱼。我们还分析了 sox9b、fbxw7、kdm1a 和 notch3 突变的斑马鱼。收集斑马鱼幼虫并通过整体免疫染色和原位杂交进行分析；收集他们的肝组织进行定量逆转录PCR。我们研究了肝细胞特异性删除 β-catenin 的小鼠（注射 AAV8-TBG-Cre 的 Ctnnb1flox/flox 小鼠），在缺乏胆碱、补充乙硫氨酸 (CDE) 饮食后，诱导 LPC 分化为肝细胞。收集肝组织并通过免疫组织化学和免疫印迹进行分析。我们对代偿性或失代偿性肝硬化患者或慢性肝衰竭急性患者 (n=15) 的肝组织进行了免疫组织化学分析。斑马鱼中 Hdac1 活性的丧失会通过增加 sox9b mRNA 的水平来阻止 LPC 向肝细胞的分化，并通过增加 cdk8 mRNA（编码 Notch 信号传导的负调节基因）的水平来减少 LPC 向 BEC 的分化。我们确定 Notch3 是调节 LPC 分化为 BEC 的受体。 Kdm1a（一种与 Hdac1 形成抑制复合物的赖氨酸脱甲基酶）活性丧失，会在 LPC 分化为肝细胞和 BEC 时产生与 Hdac1 活性丧失的斑马鱼中观察到的相同缺陷。在 CDE 饮食后，对肝细胞特异性丧失 β-连环蛋白的小鼠施用 MS-275 会损害 LPC 向肝细胞的分化。 HDAC1在肝硬化患者肝组织的反应性导管和肝细胞芽中表达。在肝细胞严重损失的斑马鱼中，Hdac1 通过 Sox9b 调节 LPC 分化为肝细胞，并通过 Cdk8、Fbxw7 和 Notch3 调节 LPC 分化为 BEC。在 CDE 饮食后肝损伤的小鼠中，LPC 分化为肝细胞也需要 HDAC1 活性。可以操纵这些途径来诱导 LPC 分化，以治疗晚期肝病患者。
Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription PCR. We studied mice in which hepatocyte-specific deletion of β-catenin (Ctnnb1flox/flox mice injected with AAV8-TBG-Cre) induces differentiation of LPCs into hepatocytes following a choline-deficient, ethionine-supplemented (CDE) diet. Liver tissues were collected and analyzed by immunohistochemistry and immunoblots. We performed immunohistochemical analyses of liver tissues from patients with compensated or decompensated cirrhosis or acute on chronic liver failure (n=15). Loss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of β-catenin impaired differentiation of LPCs into hepatocytes following the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis. Hdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury following the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.
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影响因子：
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作者：
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