Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, Chongqing 400715, China.
Institute of Developmental Biology and Regenerative Medicine, Southwest University, 2 Tiansheng Road, Beibei, Chongqing 400715, China.
Cell Rep. 2022 Apr 5;39(1):110596. doi: 10.1016/j.celrep.2022.110596.
Upon extensive hepatocyte loss or impaired hepatocyte proliferation, liver regeneration occurs via biliary epithelial cell (BEC) transdifferentiation, which includes dedifferentiation of BECs into bipotential progenitor cells (BP-PCs) and then redifferentiation of BP-PCs to nascent hepatocytes and BECs. This BEC-driven liver regeneration involves reactivation of hepatoblast markers, but the underpinning mechanisms and their effects on liver regeneration remain largely unknown. Using a zebrafish extensive hepatocyte ablation model, we perform an N-ethyl-N-nitrosourea (ENU) forward genetic screen and identify a liver regeneration mutant, liver logan (lvl), in which the telomere maintenance 2 (tel2) gene is mutated. During liver regeneration, the tel2 mutation specifically inhibits transcriptional activation of a hepatoblast marker, hematopoietically expressed homeobox (hhex), in BEC-derived cells, which blocks BP-PC redifferentiation. Mechanistic studies show that Tel2 associates with the hhex promoter region and promotes hhex transcription. Our results reveal roles of Tel2 in the BP-PC redifferentiation process of liver regeneration by activating hhex.
在广泛的肝细胞损失或受损的肝细胞增殖的情况下，肝脏再生通过胆管上皮细胞（BEC）转分化发生，其包括 BEC 去分化为双潜能祖细胞（BP-PC），然后 BP-PC 再分化为新生肝细胞和 BEC。这种 BEC 驱动的肝脏再生涉及肝母细胞标记物的重新激活，但基础机制及其对肝脏再生的影响在很大程度上仍不清楚。我们使用斑马鱼广泛的肝细胞消融模型，进行了 N-乙基-N-亚硝基脲（ENU）正向遗传筛选，并鉴定出一种肝脏再生突变体，肝脏洛根（lvl），其中端粒维持 2（tel2）基因发生突变。在肝脏再生过程中，tel2 突变特异性抑制 BEC 衍生细胞中肝母细胞标记物造血表达同源盒（hhex）的转录激活，从而阻止 BP-PC 的再分化。机制研究表明，Tel2 与 hhex 启动子区域结合并促进 hhex 转录。我们的结果揭示了 Tel2 通过激活 hhex 在肝脏再生的 BP-PC 再分化过程中的作用。
