Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish.
Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish.
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DOI：
10.1002/hep.31437
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Shin D
中科院分区：
文献类型：
--
作者：
So J;Kim M;Lee SH;Ko S;Lee DA;Park H;Azuma M;Parsons MJ;Prober D;Shin D
肝脏是一个高度再生的器官，但它的再生能力在严重的肝损伤环境中受到损害。在慢性肝病中，肝祖细胞（LPC）的数量与疾病的严重程度成比例相关，这意味着它们分化为肝细胞的效率低下会加剧疾病。此外，LPC分泌促炎细胞因子;因此，它们的长期存在会刺激炎症并诱导纤维化。在晚期肝病患者中促进LPC向肝细胞分化，肝移植是目前唯一的治疗选择，可能是一种可行的临床方法，因为这种促进产生更多功能性肝细胞，同时减少炎症和纤维化。在这里，使用斑马鱼模型的LPC介导的肝再生，我们提出了一个证明的原则，这种治疗方法，通过展示的作用，EGFR信号通路的LPC分化成肝细胞。我们发现EGFR信号的抑制通过MEK-ERK-SOX 9级联促进LPC向肝细胞的分化。EGFR或MEK/ERK的药理学抑制促进LPC向肝细胞分化以及EGFR-ERK-SOX 9轴的遗传抑制。此外，Sox 9 b在LPC中的过表达阻断了它们向肝细胞的分化。在斑马鱼肝损伤模型中，肝细胞和胆管上皮细胞都对LPC有贡献。EGFR抑制促进LPCs的分化，无论其来源。值得注意的是，EGFR抑制剂的短期治疗在长期内导致更好的肝脏恢复。EGFR-ERK-SOX 9轴在LPC介导的肝再生过程中抑制LPC向肝细胞的分化。我们建议EGFR抑制剂作为晚期肝病患者的促再生治疗药物。
The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver injury settings. In chronic liver diseases, the number of liver progenitor cells (LPCs) correlates proportionally to disease severity, implying that their inefficient differentiation into hepatocytes exacerbates the disease. Moreover, LPCs secrete pro-inflammatory cytokines; thus, their prolonged presence worsens inflammation and induces fibrosis. Promoting LPC-to-hepatocyte differentiation in patients with advanced liver disease, for whom liver transplantation is currently the only therapeutic option, may be a feasible clinical approach since such promotion generates more functional hepatocytes and concomitantly reduces inflammation and fibrosis. Here, using zebrafish models of LPC-mediated liver regeneration, we present a proof-of-principle of such therapeutics by demonstrating a role for the EGFR signaling pathway in differentiation of LPCs into hepatocytes. We found that suppression of EGFR signaling promoted LPC-to-hepatocyte differentiation via the MEK-ERK-SOX9 cascade. Pharmacological inhibition of EGFR or MEK/ERK promoted LPC-to-hepatocyte differentiation as well as genetic suppression of the EGFR-ERK-SOX9 axis. Moreover, Sox9b overexpression in LPCs blocked their differentiation into hepatocytes. In the zebrafish liver injury model, both hepatocytes and biliary epithelial cells contributed to LPCs. EGFR inhibition promoted the differentiation of LPCs regardless of their origin. Notably, short-term treatment with EGFR inhibitors resulted in better liver recovery over the long term. The EGFR-ERK-SOX9 axis suppresses LPC-to-hepatocyte differentiation during LPC-mediated liver regeneration. We suggest EGFR inhibitors as a pro-regenerative therapeutic drug for patients with advanced liver disease.
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影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.
影响因子：
2.7
作者：
Huang, Wei;Beer, Rebecca L.;Delaspre, Fabien;Wang, Guangliang;Edelman, Hannah E.;Park, Hyewon;Azuma, Mizuki;Parsons, Michael J.
通讯作者：
Parsons, Michael J.
影响因子：
82.9
作者：
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影响因子：
13.5
作者：
Lopez-Luque, Judit;Caballero-Diaz, Daniel;Fabregat, Isabel
通讯作者：
Fabregat, Isabel
影响因子：
11.2
作者：
Ling S;Chang X;Schultz L;Lee TK;Chaux A;Marchionni L;Netto GJ;Sidransky D;Berman DM
通讯作者：
Berman DM