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 Crizotinib ic50 interactions are conserved, our findings may also be relevant to human liver regeneration. (HEPATOLOGY 2010) The adult liver is unique in its intrinsic ability to regenerate through proliferation of fully differentiated cells.1 Adult hepatocytes are quiescent and normally divide only once or twice a year in mice and even less

frequently in humans.2 However, adult hepatocytes see more have the ability to divide numerous times in response to liver tissue injury or loss.3, 4 After 2/3 partial hepatectomy (2/3 PH) in mice, hepatocytes enter and progress through the cell cycle in a highly synchronized fashion.5 Every hepatocyte divides once, and every other hepatocyte divides once more to restore the liver Hydroxychloroquine clinical trial mass within 7 days.1 A complex network of cytokine and growth factor signaling between hepatocytes and other liver cell types regulates the hepatocyte cell cycle to ensure that liver regeneration is rapid and robust.6 Although microRNAs (miRNAs) have been shown to posttranscriptionally regulate genes that orchestrate proliferation in development and cancer, their role in organ regeneration is largely unknown. Recent studies in zebrafish have revealed that suppression of miR-1337 or miR-2038 is required for fin regeneration. Zebrafish fin regeneration

is mediated by stem cells that are recruited to or originate from dedifferentiation of cells residing in the injured area. In contrast, regeneration of the mammalian liver entails cell cycle entry and division of differentiated hepatocytes. Proliferating hepatocytes remain differentiated and continue to provide liver function.9 Knowing how this unique form of regeneration is regulated might enable its restoration in diseased hepatocytes and recapitulation in other, nonregenerative cell types. Here we describe the results of our analysis of the changes in miRNA expression during mouse liver regeneration, leading to the identification of miR-21 and miR-378 as regulators of organ regeneration.