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Loss of integrin αvβ8 on murine hepatocytes accelerates liver regeneration

ABSTRACT: We assess the difference in overall gene expression levels post 2/3 hepatectomy in mouse livers as a result of loss of integrin αvβ8, through microArray experiments. We hypothesized that depletion of hepatocyte integrin αvβ8 would increase hepatocyte proliferation and accelerate liver regeneration following injury. Through use of microarray experiments we identify genes that are up/down regulated only in the mice with integrin αvβ8 depletion.

ORGANISM(S): Mus musculus

PROVIDER: GSE111591 | GEO | 2018/03/09

REPOSITORIES: GEO

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Project description:Several studies indicate that adult stem cells may improve the recovery from acute tissue injury. It has been suggested that they may contribute to tissue regeneration by the release of paracrine factors promoting proliferation of tissue resident cells. However, the factors involved remain unknown. In the present study we found that microvesicles (MV) derived from human liver stem cells (HLSC) were able to stimulate in vitro proliferation and apoptosis resistance of human and rat hepatocytes. These effects required internalization of MV in the hepatocytes by an alpha4 integrin-dependent mechanism. However, when treated with RNase, MV despites their internalization were unable to induce hepatocyte proliferation and apoptosis resistance, suggesting an RNA dependent effect. Microarray analysis and quantitative RT-PCR demonstrated that MV were shuttling a specific subset of cellular mRNA, such as mRNA associated in the control of transcription, translation, proliferation and apoptosis. When administered in vivo, MV were found to accelerate the morphological and functional recovery of liver in a model of 70% hepatectomy in rats by inducing an hepatocytes proliferation that was abolished by RNase treatment. Using human AGO2 gene, which is shuttled by MV, as a reporter gene, we found the expression of human AGO2 mRNA and protein in the liver of hepatectomized rats treated with MV. This suggest a translation of the MV shuttled mRNA within hepatocytes of treated rats. Conclusion: these results suggest that MV derived from HLSC may activate a proliferative program in remnant hepatocytes after hepatectomy by a horizontal transfer of specific mRNA subsets. MV contained mRNA was submitted to microarray analysis not to define the amount of mRNA but only to define which transcripts were present. Total RNA was prepared from two independent preparation of vesicles. 250, 500 and 1000 ngs from each preparation were transformed in biotin-labeled cRNA. A simple statistical linear model was used to identify transcript signals linearly correlated to the increment of total RNA concentration used to prepare cRNA.

Project description:Geier2011 - Integrin activation Rule based model that integrates the available data to test the biololical hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation. This model is described in the article: A computational analysis of the dynamic roles of talin, Dok1, and PIPKI for integrin activation. Geier F, Fengos G, Iber D. PLoS One. 2011;6(11):e24808. Abstract: Integrin signaling regulates cell migration and plays a pivotal role in developmental processes and cancer metastasis. Integrin signaling has been studied extensively and much data is available on pathway components and interactions. Yet the data is fragmented and an integrated model is missing. We use a rule-based modeling approach to integrate available data and test biological hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation. The detailed biochemical characterization of integrin signaling provides us with measured values for most of the kinetics parameters. However, measurements are not fully accurate and the cellular concentrations of signaling proteins are largely unknown and expected to vary substantially across different cellular conditions. By sampling model behaviors over the physiologically realistic parameter range we find that the model exhibits only two different qualitative behaviors and these depend mainly on the relative protein concentrations, which offers a powerful point of control to the cell. Our study highlights the necessity to characterize model behavior not for a single parameter optimum, but to identify parameter sets that characterize different signaling modes. This model is hosted on BioModels Database and identified by: MODEL1208280001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Loss of integrin αvβ8 on murine hepatocytes accelerates liver regeneration

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