MicroRNAs control hepatocyte proliferation during liver regeneration

Authors

  • Guisheng Song,

    1. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
    2. Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA
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    • G.S. and A.D.S. share first authorship. G.R.R. and R.N. share second authorship.

  • Amar Deep Sharma,

    1. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
    2. Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA
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    • G.S. and A.D.S. share first authorship. G.R.R. and R.N. share second authorship.

  • Garrett R. Roll,

    1. Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA
    2. Liver Center, University of California San Francisco, San Francisco, CA
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    • G.S. and A.D.S. share first authorship. G.R.R. and R.N. share second authorship.

  • Raymond Ng,

    1. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
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    • G.S. and A.D.S. share first authorship. G.R.R. and R.N. share second authorship.

  • Andrew Y. Lee,

    1. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
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  • Robert H. Blelloch,

    1. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
    2. Department of Urology, University of California San Francisco, San Francisco, CA
    3. Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA
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  • Niels M. Frandsen,

    1. Exiqon A/S, Vedbaek, Denmark
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  • Holger Willenbring

    Corresponding author
    1. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
    2. Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA
    3. Liver Center, University of California San Francisco, San Francisco, CA
    • Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Department of Surgery, Division of Transplantation, University of California San Francisco, 513 Parnassus Avenue, S1457B, Campus Box 0525, San Francisco, CA 94143
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    • fax: (415) 514 2346


  • 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.

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. (HEPATOLOGY 2010)

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