Article

MicroRNAs Control Hepatocyte Proliferation During Liver Regeneration

Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143, USA.
Hepatology (Impact Factor: 11.06). 05/2010; 51(5):1735-43. DOI: 10.1002/hep.23547
Source: PubMed

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 G(1) 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.

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Available from: Andrew Lee, Jun 20, 2014
    • "This transdifferentiation potential has been extensively studied in the context of regenerating the retina from the pigmented OC derivatives: RPE, ciliary body and iris (Luz- Madrigal et al., 2014; Tropepe et al., 2000; Wohl et al., 2012). miRNAs are central regulators of developmental processes including tissue regeneration (Song et al., 2010a; Thatcher et al., 2008) and several miRNAs have been documented to play key roles in maintaining cell fate in multiple lineages, as shown for miR-142 in the generation of hematopoietic stem cells and for miR-375 in the endocrine beta-cell lineage (Kaspi et al., 2014; Nimmo et al., 2013; Poy et al., 2004). "
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    • "This transdifferentiation potential has been extensively studied in the context of regenerating the retina from the pigmented OC derivatives: RPE, ciliary body and iris (Luz- Madrigal et al., 2014; Tropepe et al., 2000; Wohl et al., 2012). miRNAs are central regulators of developmental processes including tissue regeneration (Song et al., 2010a; Thatcher et al., 2008) and several miRNAs have been documented to play key roles in maintaining cell fate in multiple lineages, as shown for miR-142 in the generation of hematopoietic stem cells and for miR-375 in the endocrine beta-cell lineage (Kaspi et al., 2014; Nimmo et al., 2013; Poy et al., 2004). "
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    • "Interestingly, as noted below, increased expression of miR-26a can suppress tumour growth arising from c-MYC overexpression (Kota et al., 2009), highlighting miR-26a as an important regulator of hepatocyte proliferation. Repression of miR-378 was also seen during the first 18 h after PH and miR-378 inhibited Odc1 (Table 1), which controls of DNA synthesis in hepatocytes (Song et al., 2010). Other studies have reported decreases in miRs-22a, 30b, let-7 family members, and, 122a, and 150 within 12–48 h after PH (Chen et al., 2011b; Yu et al., 2013). "
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