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LncRNA GHET1 from bone mesenchymal stem cell-derived exosomes improves doxorubicin-induced pyroptosis of cardiomyocytes by mediating NLRP3.

ABSTRACT: Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX-induced cardiotoxicity. Bone mesenchymal stem cell-derived exosomes (BMSC-Exos) and endothelial progenitor cells-derived exosomes (EPC-Exos) have a protective role in the myocardium. Here we found that BMSC-Exos could improve DOX-induced cardiotoxicity by inhibiting pyroptosis, but EPC-Exos couldn't. Compared with EPCs-Exo, BMSC-Exo-overexpressing lncRNA GHET1 more effectively suppressed pyroptosis, protecting against DOX-induced cardiotoxicity. Further studies showed that lncRNA GHET1 effectively decreased the expression of Nod-like receptor protein 3 (NLRP3), which plays a vital role in pyroptosis by binding to IGF2 mRNA-binding protein 1 (IGF2BP1), a non-catalytic posttranscriptional enhancer of NLRP3 mRNA. In summary, lncRNA GHET1 released by BMSC-Exo ameliorated DOX-induced pyroptosis by targeting IGF2BP1 to reduce posttranscriptional stabilization of NLRP3.

SUBMITTER: Zhai X

PROVIDER: S-EPMC11330485 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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LncRNA GHET1 from bone mesenchymal stem cell-derived exosomes improves doxorubicin-induced pyroptosis of cardiomyocytes by mediating NLRP3.

Zhai Xiaoya X Zhou Jiedong J Huang Xingxiao X Weng Jingfan J Lin Hui H Sun Shimin S Chi Jufang J Meng Liping L

Scientific reports 20240817 1

Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX-induced cardiotoxicity. Bone mesenchymal stem cell-derived exosomes (BMSC-Exos) and endothelial progenitor cells-derived exosomes (EPC-Exos) have a protective role in the myocardium. Here we found that BMSC-Exos could improve DOX-induced cardio ...[more]

PMID: 39154102

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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

LncRNA GHET1 from bone mesenchymal stem cell-derived exosomes improves doxorubicin-induced pyroptosis of cardiomyocytes by mediating NLRP3.

Publications

LncRNA GHET1 from bone mesenchymal stem cell-derived exosomes improves doxorubicin-induced pyroptosis of cardiomyocytes by mediating NLRP3.

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