MicroRNAs control hepatocyte proliferation during liver regeneration

Guisheng Song, Amar Deep Sharma, Garrett R. Roll, Raymond Ng, Andrew Y. Lee, Robert H. Blelloch, Niels M. Frandsen, Holger Willenbring

Research output: Contribution to journalArticle

158 Scopus citations

Abstract

MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G1 to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH. Conclusion: Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration.

Original languageEnglish (US)
Pages (from-to)1735-1743
Number of pages9
JournalHepatology
Volume51
Issue number5
DOIs
StatePublished - May 2010

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    Song, G., Sharma, A. D., Roll, G. R., Ng, R., Lee, A. Y., Blelloch, R. H., Frandsen, N. M., & Willenbring, H. (2010). MicroRNAs control hepatocyte proliferation during liver regeneration. Hepatology, 51(5), 1735-1743. https://doi.org/10.1002/hep.23547