Successful and failed human liver regeneration are characterized by the coordinated expression of distinct microRNAs
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ABSTRACT: The liverM-bM-^@M-^Ys remarkable capacity to regenerate allows it to carry out vital life-supporting functions despite unrelenting pathogen and toxin-induced injury. Unchecked, this capability also leads to cirrhosis, a burgeoning global disease burden. Existing animal models only partially recapitulate human liver regeneration, which hitherto has not been systematically studied. We investigated human liver regeneration in a unique model of liver transplantation. Here we show coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. Failed regeneration is associated with distinct miRNAs enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of three miRNAs whose downregulation is associated with successful regeneration, induced proliferation in vitro. Our data indicate that human liver regeneration is orchestrated by distinct miRNAs determining cell cycle fate. Their manipulation may obviate the need for transplantation by enforcing successful regeneration in the liver and other solid organs. We compared a group of seven patients with successful regeneration (RG) after auxiliary liver transplant (ALT) to four patients who also had ALT but failed to regenerate (NRG). Regeneration was quantified by volume expansion using radiographic imaging; functional recovery was assessed using nuclear isotope scanning and hepatocellular regeneration using histology. Based on histological assessment, three time points were selected for both groups (RG and NRG). Biopsies were taken at the time of transplant and at different intervals post-transplant. Since sample acquisition was driven by clinical necessity, widely discrepant time intervals existed between T=1, T=2 and T=3 for the patients. RNA was extracted from archived histology samples of the RG and NRG, and miRNA expression was analysed using the Affymetrix GeneChip miRNA 1.0 assays. This submission does not include NRG samples taken at time point 3.
ORGANISM(S): Homo sapiens
SUBMITTER: siamak salehi
PROVIDER: E-GEOD-36146 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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