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Expression of antisense of microRNA-26a-5p in mesenchymal stem cells increases their therapeutic effects against cirrhosis.

ABSTRACT: Hepatocyte growth factor (HGF) is a potent mitogen for mature hepatocytes, and has been shown to prevent cirrhosis during liver regeneration. Transplantation of mesenchymal stem cells (MSCs) reduces the development of cirrhosis after liver injury. However, the production and secretion of transplanted MSCs in liver were not studied yet. Here we found that the MSCs expressed low levels of HGF protein, but surprisingly high levels of HGF mRNA. Further investigation using bioinformatics analyses and luciferase reporter assay showed that MSCs expressed high levels of microRNA-26a-5p (miR-26a-5p), which targeted 3'-UTR of HGF mRNA to inhibit its protein translation. In vivo, miR-26a-5p-depleted MSCs were transplanted into mice with carbon tetrachloride (CCl₄)-induced cirrhosis. We found that suppression of miR-26a-5p in MSCs further ameliorated the severity of liver fibrosis, reduced the portal hypertension and sodium retention, compared to transplantation of control MSCs. Hence, our study suggests that suppression of miR-26a-5p in MSCs may improve their therapeutic effects against cirrhosis through increasing HGF production.

SUBMITTER: Chen L

PROVIDER: S-EPMC5376040 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Expression of antisense of microRNA-26a-5p in mesenchymal stem cells increases their therapeutic effects against cirrhosis.

Chen Li L Zeng Wenhuan W Yang Bo B Cui Xiang X Feng Cong C Wang Lili L Wang Hao H Zhou Xuan X Li Peng P Lv Faqin F Li Tanshi T

American journal of translational research 20170315 3

Hepatocyte growth factor (HGF) is a potent mitogen for mature hepatocytes, and has been shown to prevent cirrhosis during liver regeneration. Transplantation of mesenchymal stem cells (MSCs) reduces the development of cirrhosis after liver injury. However, the production and secretion of transplanted MSCs in liver were not studied yet. Here we found that the MSCs expressed low levels of HGF protein, but surprisingly high levels of HGF mRNA. Further investigation using bioinformatics analyses and ...[more]

PMID: 28386375

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Project description:BackgroundIntervertebral disc degeneration (IVDD) is the breakdown of the discs supporting the vertebrae. It is one of the most frequent causes of back pain worldwide. Currently, the clinical interventions for IVDD are mainly focused on symptom releases. Thus, new therapeutic options are needed.MethodsNucleus pulposus (NP) samples were obtained from 20 patients experiencing IVDD and 10 healthy volunteers compared for mRNA N6-methyladenosine (m6A) mRNA modification as well as methyltransferase (METT) like METTL3, METTL14, and Wilms' tumor 1-associated protein mRNA and protein abundance following exosomes exposure from mesenchymal stem cells. In addition, microRNA expressions were also compared. The correlation between the NLR family pyrin domain containing 3 (NLRP3) and METTL14 was measured by luciferase reporter assay. Cytokines were evaluated using an enzyme-linked immunosorbent assay. METTL14, NLRP3, and insulin-like growth factor 2 mRNA-binding protein 2 mRNAs were measured via a quantitative reverse transcription-polymerase chain reaction. Protein was assayed using western blots. Cell death was assessed by propidium iodide staining, lactate dehydrogenase release, gasdermin-N domain abundance, and caspase-1 activation.ResultsThe human umbilical cord mesenchymal stem cell (hucMSC) exosomes were found to effectively improve the viability of NP cells and protect them from pyroptosis through targeting METTL14, with a methyltransferase catalyzing m6A modification. METTL14 was highly present in NP cells from IVDD patients, which stabilize NLRP3 mRNA in an IGFBP2-dependent manner. The elevated NLRP3 levels result in the increase of interleukin 1β (IL-1β) and IL-18 levels and trigger pyroptotic NP cell death. Such pathogenic axis could be blocked by hucMSC exosomes, which directly degrade METTL14 through exosomal miR-26a-5p.ConclusionsThe results of the current study revealed the beneficial effects of hucMSC exosomes on NP cells and determined a potential mechanism inducing IVDD.

Dataset Information

Expression of antisense of microRNA-26a-5p in mesenchymal stem cells increases their therapeutic effects against cirrhosis.

Publications

Expression of antisense of microRNA-26a-5p in mesenchymal stem cells increases their therapeutic effects against cirrhosis.

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