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Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p.

ABSTRACT: Pathways of liver fibrosis are controlled by connective tissue growth factor (CCN2). In this study, CCN2 was identified as a target of miR-199a-5p, which was principally expressed in quiescent mouse hepatic stellate cells (HSCs) and directly suppressed production of CCN2. Up-regulated CCN2 expression in fibrotic mouse livers or in activated primary mouse HSCs was associated with miR-199a-5p down-regulation. MiR-199a-5p in quiescent mouse HSCs inhibited the activity of a wild-type CCN2 3' untranslated region (3'-UTR) but not of a mutant CCN2 3'-UTR lacking the miR-199a-5p-binding site. In activated mouse HSCs, CCN2, ?-smooth muscle actin, and collagen 1(?1) were suppressed by a miR-199a-5p mimic, whereas in quiescent mouse HSCs, the inhibited CCN2 3'-UTR activity was blocked by a miR-199a-5p antagomir. CCN2 3'-UTR activity in human HSCs was reduced by a miR-199a-5p mimic. MiR-199a-5p was present at higher levels in exosomes from quiescent versus activated HSCs. MiR-199a-5p-containing exosomes were shuttled from quiescent mouse HSCs to activated mouse HSCs in which CCN2 3'-UTR activity was then suppressed. Exosomes from quiescent HSCs caused miR-199a-5p-dependent inhibition of CCN2, ?-smooth muscle actin, or collagen 1(?1) in activated HSCs in vitro and bound to activated HSCs in vivo. Thus, CCN2 suppression by miR-199a-5p accounts, in part, for low-level fibrogenic gene expression in quiescent HSCs and causes dampened gene expression in activated HSCs after horizontal transfer of miR-199a-5p in exosomes from quiescent HSCs.

SUBMITTER: Chen L

PROVIDER: S-EPMC5222964 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p.

Chen Li L Chen Ruju R Velazquez Victoria M VM Brigstock David R DR

The American journal of pathology 20160921 11

Pathways of liver fibrosis are controlled by connective tissue growth factor (CCN2). In this study, CCN2 was identified as a target of miR-199a-5p, which was principally expressed in quiescent mouse hepatic stellate cells (HSCs) and directly suppressed production of CCN2. Up-regulated CCN2 expression in fibrotic mouse livers or in activated primary mouse HSCs was associated with miR-199a-5p down-regulation. MiR-199a-5p in quiescent mouse HSCs inhibited the activity of a wild-type CCN2 3' untrans ...[more]

PMID: 27662798

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Project description:Background & aimsMethyl-CpG binding protein 2, MECP2, which binds to methylated regions of DNA to regulate transcription, is expressed by hepatic stellate cells (HSCs) and is required for development of liver fibrosis in mice. We investigated the effects of MECP2 deletion from HSCs on their transcriptome and of phosphorylation of MECP2 on HSC phenotype and liver fibrosis.MethodsWe isolated HSCs from Mecp2-/y mice and wild-type (control) mice. HSCs were activated in culture and used in array analyses of messenger RNAs and long noncoding RNAs. Kyoto Encyclopedia of Genes and Genomes pathway analyses identified pathways regulated by MECP2. We studied mice that expressed a mutated form of Mecp2 that encodes the S80A substitution, MECP2S80, causing loss of MECP2 phosphorylation at serine 80. Liver fibrosis was induced in these mice by administration of carbon tetrachloride, and liver tissues and HSCs were collected and analyzed.ResultsMECP2 deletion altered expression of 284 messenger RNAs and 244 long noncoding RNAs, including those that regulate DNA replication; are members of the minichromosome maintenance protein complex family; or encode CDC7, HAS2, DNA2 (a DNA helicase), or RPA2 (a protein that binds single-stranded DNA). We found that MECP2 regulates the DNA repair Fanconi anemia pathway in HSCs. Phosphorylation of MECP2S80 and its putative kinase, HAS2, were induced during transdifferentiation of HSCs. HSCs from MECP2S80 mice had reduced proliferation, and livers from these mice had reduced fibrosis after carbon tetrachloride administration.ConclusionsIn studies of mice with disruption of Mecp2 or that expressed a form of MECP2 that is not phosphorylated at S80, we found phosphorylation of MECP2 to be required for HSC proliferation and induction of fibrosis. In HSCs, MECP2 regulates expression of genes required for DNA replication and repair. Strategies to inhibit MECP2 phosphorylation at S80 might be developed for treatment of liver fibrosis.

Dataset Information

Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p.

Publications

Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p.

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