Unknown,Transcriptomics,Genomics,Proteomics

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Successful and failed human liver regeneration are characterized by the coordinated expression of distinct microRNAs

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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Human liver regeneration is characterized by the coordinated expression of distinct microRNA governing cell cycle fate.

Salehi S S Brereton H C HC Arno M J MJ Darling D D Quaglia A A O'Grady J J Heaton N N Aluvihare V R VR

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20130306 5

In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long-term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver reg ...[more]

PMID: 23465054

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Project description:Recurrent hepatitis C virus (rHCV) is universal post-liver transplantation (LT), with accelerated fibrosis rates compared to non-transplanted patients. rHCV is associated with increased mortality and morbidity post-transplant and is a leading indication for re-transplantation. We hypothesized that miRNA expression profiles from liver grafts can distinguish severity of HCV recurrence and differentiate this from acute cellular rejection (ACR). Methods Using microarrays, we characterized global microRNA (miRNA) expression from patients with slow HCV fibrosis progression (F<2 Ishak), fast HCV fibrosis progression (FM-bM-^IM-%2 Ishak), ACR and non-HCV transplanted patients. Selected miRNA were analysed by quantitative PCR (qPCR) using both liver tissue and serum samples. Results We demonstrated changes in miRNA expression in patients with slow HCV fibrosis progression that were anti-fibrogenic, anti-angiogenic and anti-inflammatory in comparison to patients with fast HCV fibrosis progression. miRNA-146a, miRNA-19a, miRNA- 20a and miRNA-let-7e expression were increased in the slow HCV fibrosis progression group. In addition, comparison of patients with fast HCV progression against patients with ACR identified pro-fibrogenic pathways. qPCR analysis on liver tissue and serum confirmed the up-regulation of miRNAs in the slow HCV fibrosis progression group. Conclusion We demonstrate specific miRNA expression signatures that distinguish rate of progression of HCV recurrence and ACR post M-bM-^@M-^Sliver transplantation. Pathway analysis indicates that specific miRNA may play a regulatory role in these processes. The miRNAs identified may act as potential biomarkers for HCV recurrence post-LT and help distinguish between ACR and recurrent HCV. We compared 29 patients in total; 11 patients with slow HCV fibrosis progression, 9 patients with fast HCV fibrosis progression, 5 patients with acute cellular rejection and 4 HCV negative patients with normal liver histology that acted as controls. RNA was extracted from archived histology samples of the RG and NRG and miRNA expression was analysed using the affymetrix Genechip miRNA 2.0 assays.

Dataset Information

Successful and failed human liver regeneration are characterized by the coordinated expression of distinct microRNAs

Publications

Human liver regeneration is characterized by the coordinated expression of distinct microRNA governing cell cycle fate.

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