Hypoxic Preconditional Engineering Small Extracellular Vesicles Promoted Intervertebral Disc Regeneration by Activating Mir-7-5p/NF-Κb/Cxcl2 Axis

Advanced Science, 2023 · DOI: 10.1002/advs.202304722 · Published: October 23, 2023

Regenerative Medicine Genetics Orthopedics

Simple Explanation

Chronic lower back pain is often caused by the degradation of intervertebral discs (IVD). This study explores a novel approach using small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) that have been preconditioned in a low-oxygen (hypoxic) environment to promote IVD regeneration. These hypoxic preconditional engineering sEVs (HP-sEVs) were found to reduce inflammation, enhance the proliferation of cells in the nucleus pulposus (NP), and boost the synthesis of proteoglycans and collagen, which are essential components of the IVD. The therapeutic effect of HP-sEVs involves delivering a specific microRNA (miR-7-5p), which suppresses the production of p65 and inhibits Cxcl2 production, leading to improved IVD regeneration and alleviation of chronic lower back pain.

Study Duration

6 Weeks

Participants

SD rats, hUCMSCs, NP cells

Evidence Level

Level 5, In vitro and in vivo studies

Key Findings

1
Hypoxic preconditioning enhances the therapeutic function of MSC-derived sEVs for IVD regeneration.
2
HP-sEVs promote ECM regeneration by delivering miR-7-5p, which inhibits the NF-κB/Cxcl2 signaling pathway.
3
In vivo, HP-sEVs demonstrate robust therapeutic effects in promoting IVD regeneration through miR-7-5p delivery.

Research Summary

This study investigates the use of hypoxic preconditioning to improve the therapeutic function of MSC-derived sEVs for treating IVD degeneration and chronic lower back pain. HP-sEVs were found to alleviate inflammation, enhance NP cell proliferation, and promote ECM regeneration both in vitro and in vivo. The mechanism involves the delivery of miR-7-5p by HP-sEVs, which suppresses the NF-κB/Cxcl2 signaling pathway, leading to improved IVD regeneration.

Practical Implications

Therapeutic Strategy

HP-sEVs offer a novel therapeutic strategy for treating IVD degradation and associated chronic lower back pain.

Mechanism Understanding

The study enhances understanding of the mechanism-of-action of HP-sEVs in IVD regeneration, particularly through the miR-7-5p/NF-κB/Cxcl2 axis.

Clinical Translation Potential

HP-sEV-based therapy may serve as a promising treatment pending further pharmacokinetic analysis, dosimetry optimization, and large-scale production protocols.

Study Limitations

1
Need for spatiotemporal distribution analysis of HP-sEVs after injection.
2
Requirement for rigorous optimization of HP-sEVs dosage in animal models.
3
Necessity of developing large-scale HP-sEVs production for clinical translation.

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