G.S. and A.D.S. share first authorship. G.R.R. and R.N. share second authorship.
MicroRNAs control hepatocyte proliferation during liver regeneration†
Article first published online: 28 JAN 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Volume 51, Issue 5, pages 1735–1743, May 2010
How to Cite
Song, G., Sharma, A. D., Roll, G. R., Ng, R., Lee, A. Y., Blelloch, R. H., Frandsen, N. M. and Willenbring, H. (2010), MicroRNAs control hepatocyte proliferation during liver regeneration. Hepatology, 51: 1735–1743. doi: 10.1002/hep.23547
Potential conflict of interest: Nothing to report.
H.W. received grant support from the California Institute for Regenerative Medicine, American Liver Foundation, and American Society of Transplantation. G.R. was supported by a fellowship from the NRSA Hepatology Training Grant at UCSF. R.N. was supported by a scholarship from the Agency of Science Technology and Research (A*STAR) Singapore.
- Issue published online: 22 APR 2010
- Article first published online: 28 JAN 2010
- Accepted manuscript online: 28 JAN 2010 12:00AM EST
- Manuscript Accepted: 20 DEC 2009
- Manuscript Received: 9 OCT 2009
- California Institute for Regenerative Medicine, American Liver Foundation, and American Society of Transplantation
- NRSA Hepatology Training Grant at UCSF
- Agency of Science Technology and Research (A*STAR) Singapore
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. (HEPATOLOGY 2010)