Graduate Institution of Clinical Medical Science, and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 40403.
Department of Trauma and Critical Care, Changhua Christian Hospital, Changhua, Taiwan.
Theranostics. 2018 Apr 9;8(10):2672-2682. doi: 10.7150/thno.23624. eCollection 2018.
Improving liver regeneration (LR) capacity and thereby liver function reserve is a critical bridging strategy for managing liver failure patients. Since estrogen signaling may participate in LR, our aim was to characterize the roles of ERα and ERβ in LR. LR capacity and estradiol levels following 2/3 partial hepatectomy (PHx) were compared in ERα-KO or ERβ-KO vs. wildtype mice. The ERα- or ERβ-related transcriptome and interactome were analyzed from regenerating livers, and then bioinformatics was used for pathway discovery and analysis of interactome-transcriptome relationships. Human hepatic progenitors (HepRG cells) and mouse Hepa1-6 hepatocytes were used to elucidate molecular interactions and functions. This paper demonstrated that estrogen signals orchestrate hepatic repopulation and differentiation distinct transcriptome patterns governed by ERα or ERβ. Cell repopulation pathway was associated with the ERα-transcriptome, but cell differentiation and metabolic function were associated with the ERβ transcriptome. Mechanistic studies linking ERs interactomes and transcriptomes discovered that ERα-Chd1 interaction promoted cell growth by upregulating Ssxb6, Crygc, and Cst1; and, ERβ-Ube3a interaction facilitated hepatic progenitor cell differentiation to hepatocytes and cholangiocytes, specifically by upregulating Ifna5. ERα and ERβ orchestrate liver cell proliferation and differentiation respectively, thereby promoting LR.
提高肝脏再生 (LR) 能力，从而提高肝功能储备，是治疗肝功能衰竭患者的关键桥梁策略。由于雌激素信号可能参与 LR，我们的目的是研究 ERα 和 ERβ 在 LR 中的作用。我们比较了 ERα-KO 或 ERβ-KO 与野生型小鼠在 2/3 部分肝切除 (PHx) 后 LR 能力和雌二醇水平。从再生肝脏中分析 ERα 或 ERβ 相关的转录组和相互作用组，然后进行生物信息学分析以发现途径并分析相互作用组-转录组关系。使用人肝祖细胞 (HepRG 细胞) 和小鼠 Hepa1-6 肝细胞阐明分子相互作用和功能。本文证明了雌激素信号协调肝再殖和分化，由 ERα 或 ERβ 控制不同的转录组模式。细胞再殖途径与 ERα-转录组相关，但细胞分化和代谢功能与 ERβ 转录组相关。将 ERs 相互作用组和转录组联系起来的机制研究发现，ERα-Chd1 相互作用通过上调 Ssxb6、Crygc 和 Cst1 促进细胞生长；ERβ-Ube3a 相互作用促进肝祖细胞向肝细胞和胆管细胞分化，特别是通过上调 Ifna5。ERα 和 ERβ 分别协调肝细胞的增殖和分化，从而促进 LR。
