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Theranostics 2018; 8(10):2672-2682. doi:10.7150/thno.23624 This issue Cite

Research Paper

Estrogen receptors orchestrate cell growth and differentiation to facilitate liver regeneration

Ta-Lun Kao^1,2, Yu-Ping Kuan³, Wei-Chung Cheng¹, Wei-Chun Chang³, Long-Bin Jeng^1,3, Shuyuan Yeh^4✉, Wen-Lung Ma^1,3,5✉

1. Graduate Institution of Clinical Medical Science, and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 40403
2. Department of Trauma and Critical Care, Changhua Christian Hospital, Changhua, Taiwan;
3. Sex Hormone Research Center, Organ Transplantation Center, and Department of OBs & GYN, China Medical University Hospital, Taichung, Taiwan 40403.
4. Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
5. Department of OBS & GYN, BenQ Medical Center, Nanjing Medical University, Suzhou, Jiangsu Province, China 215004.

✉ Corresponding author: Wen-Lung Ma, PhD. Tel: +886-975681032; email: maverickcmu.edu.tw; Address: 91 Xueshi Rd., North District, Taichung, Taiwan 40403. Shuyuan Yeh, PhD. email: shuyuan_yehrochester.edu

Abstract

Background and Aims: 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.

Methods: LR capacity and estradiol levels following 2/3^rd 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.

Results: This paper demonstrated that estrogen signals orchestrate hepatic repopulation and differentiation via 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.

Conclusions: ERα and ERβ orchestrate liver cell proliferation and differentiation respectively, thereby promoting LR.

Keywords: estrogen receptor, liver regeneration, liver failure

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