Dataset Information

Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying circ_0050205 Attenuate Intervertebral Disc Degeneration

ABSTRACT:

Objective

It has been reported that bone marrow mesenchymal stem cells (BMSCs) are a potential source of autologous stem cells to support the nucleus pulposus (NP) regeneration in intervertebral disc degeneration (IDD). Herein, we aim to study the mechanism underlying the effects of BMSC-derived extracellular vesicles (BMSC-EVs) on nucleus pulposus cells (NPCs) in IDD.

Methods

EVs were isolated from BMSCs. An IDD model was surgically established in C57BL/6J mice. NPCs were exposed to tBHP to establish an IDD cell model. RNA sequencing was performed to identify differentially expressed circRNAs in NP tissues harvested from mice with IDD. Interactions among circ_0050205, miR-665, and GPX4 were validated, and different interventions were used to study the roles of these molecules in NPC biological functions.

Results

BMSC-EVs promoted NPC survival and inhibited NPC apoptosis and extracellular matrix (ECM) degradation. circ_0050205 expression was downregulated in the NP tissues of IDD mice, and BMSC-EVs facilitated NPC survival and suppressed ECM degradation in NPCs by transferring circ_0050205. circ_0050205 sponged miR-665 and upregulated GPX4 expression. BMSC-EVs expressing circ_0050205 promoted NPC survival-inhibited ECM degradation in NPCs and alleviated IDD in mice via the miR-665/GPX4 axis.

Conclusion

In conclusion, BMSC-EVs promoted NPC survival-inhibited ECM degradation in NPCs and attenuated IDD progression via the circ_0050205/miR-665/GPX4 axis.

SUBMITTER: Yu X

PROVIDER: S-EPMC9277161 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGrowing evidence has suggested the role of stem cell-derived small extracellular vesicles (sEVs) in intervertebral disc degeneration (IVDD). The cargo sorting of sEVs, particularly miRNAs, may be influenced when the donor cell is subjected to oxidative stress. Here, we discovered that miRNAs containing specific motifs are selectively sorted into intraluminal vesicles within mesenchymal stem cells (MSCs) in response to oxidative stress.MethodsAnalysis of miRNA cargoes in sEVs derived from normal MSCs (C-sEVs) or stressed MSCs (T-sEVs) was conducted using miRNA sequencing. Differential expressed miRNAs in sEVs and the identification of motifs were evaluated through bioinformatics analysis. Protein binding was assessed using immunofluorescent staining and immunoprecipitation analysis. Additionally, RNA pull down and RNA immunoprecipitation (RIP) immunoprecipitation were employed to determine the binding between miRNAs and proteins. The effects of C-sEVs and T-sEVs on IVDD were compared by detecting the expression levels of phenotypic genes in vitro or histological evaluation in vivo.ResultsThe sorting process of miRNAs is mediated by the nucleocytoplasmic transport of heterogeneous nuclear ribonucleoproteins, which in turn facilitates the phosphorylation of SNAP25 and promotes the transport and secretion of sEVs. Additionally, CHMP1B plays a role in membrane repair and protects against cell ferroptosis upon oxidative stress, concurrently affecting the release of sEVs. Notably, stem cell-derived sEVs associated with ferroptosis impair the therapeutic efficacy for IVDD. However, the application of engineered sEVs containing a specific miRNA inhibitor exhibits the potential to reinstate the therapeutic efficacy for IVDD both in vitro and in vivo.ConclusionsTaken together, our findings shed light on the mechanism of miRNAs sorting into sEVs and offer new insights for the optimization of sEV-based treatments during intervertebral disc regeneration. regeneration.