Abstract
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.
Highlights
Intervertebral disc degeneration (IVDD) is the breakdown of the pads between vertebrae, which provide cushion and mechanical support for the vertebrae
N6-methyladenosine (m6A) is the most common endogenous RNA modification in mammalian cells and can efficiently regulate RNA abundance and gene expression levels by modulating a variety of aspects including RNA secondary structure and metabolisms (Huang et al 2018). It is mediated by a methyltransferase complex or writers, including methyltransferase (METTL) like METTL3, METTL14, and Wilms’ tumor 1-associated protein (WTAP) (Shen et al 2020)
HucMSC promotes cell viability and inhibits expression of methyltransferases in Human NP cells (HNPC) Before addressing the function of MSCs, the human umbilical cord mesenchymal stem cell (hucMSC) was first determined to continue to fulfill the minimal criteria for defining MSCs
Summary
Intervertebral disc degeneration (IVDD) is the breakdown of the pads (discs) between vertebrae, which provide cushion and mechanical support for the vertebrae. Yuan et al Mol Med (2021) 27:91 called the nucleus pulpous (NP), which is surrounded by a tough, fibrous cartilage ring called the annulus fibrosis (Colombier et al 2014) They are a common site for injury and degradation despite the robust structure of the intervertebral discs. N6-methyladenosine (m6A) is the most common endogenous RNA modification in mammalian cells and can efficiently regulate RNA abundance and gene expression levels by modulating a variety of aspects including RNA secondary structure and metabolisms (Huang et al 2018) It is mediated by a methyltransferase complex or writers, including methyltransferase (METTL) like METTL3, METTL14, and Wilms’ tumor 1-associated protein (WTAP) (Shen et al 2020).
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