Estrogen receptors orchestrate cell growth and differentiation to facilitate liver regeneration

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/...

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Bibliographic Details
Published in:Theranostics 2018-01, Vol.8 (10), p.2672-2682
Main Authors: Kao, Ta-Lun, Kuan, Yu-Ping, Cheng, Wei-Chung, Chang, Wei-Chun, Jeng, Long-Bin, Yeh, Shuyuan, Ma, Wen-Lung
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
Cell Line, Tumor
Female
HEK293 Cells
Hepatocytes - cytology
Hepatocytes - metabolism
Humans
Liver - cytology
Liver - metabolism
Liver - physiology
Liver Regeneration
Male
Mice
Receptors, Estrogen - metabolism
Research Paper
Stem Cells - cytology
Stem Cells - metabolism
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Summary: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.
ISSN:1838-7640
DOI:10.7150/thno.23624