Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration

Yuxin Jin ¹, Ouqiang Wu ¹, Qizhu Chen ¹

¹Department of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
²Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
³Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
⁴Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 5/F Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China.
⁵Spine Unit, The Royal Orthopaedic Hospital, Bristol Road South, Northfield, Birmingham, B31 2AP, UK.
⁶The minimaly invasive Brain and Spine Institute, Department of Neurosurgery, State University of New York Upstate medical university, 475 Irving Ave, #402, Syracuse, NY, 13210, USA.
⁷School of Chemistry, Damghan University, Damghan, 36716-45667, Iran.
⁸University Centre for Research & Development, Chandigarh University, Mohali, Punjab, 140413, India.
⁹Department of Biomaterials, Saveetha Dental College and Hospitals, SIMATS, Saveetha University, Chennai, 600077, India.
¹⁰Department of Orthopaedics, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.

⁰Department of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.

Advanced Science (weinheim, Baden-Wurttemberg, Germany) +

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July 8, 2024

View abstract on PubMed

Summary

Bone marrow mesenchymal stem cell exosomes deliver BNIP3 to nucleus pulposus cells, restoring mitochondrial function and alleviating intervertebral disc degeneration. This approach targets the BNIP3/ANXA2/TFEB pathway for effective IVDD treatment.

Area Of Science

Biomedical Engineering
Cell Biology
Regenerative Medicine

Background

Intervertebral disc degeneration (IVDD) is linked to nucleus pulposus cell (NPC) aging and impaired mitochondrial dynamics.
BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) deficiency correlates with NPC senescence and compromised mitochondrial quality control.

Purpose Of The Study

To investigate the therapeutic potential of bone marrow mesenchymal stem cell (BMSC)-derived exosomes enriched with BNIP3 for IVDD.
To elucidate the mechanism by which BNIP3 delivery impacts NPC aging and mitochondrial function.

Main Methods

BMSCs were stimulated under hypoxia to produce exosomes containing BNIP3.
These exosomes were administered to NPCs to assess effects on mitochondrial autophagic flux and senescence.
The interaction between BNIP3, annexin A2 (ANXA2), and transcription factor EB (TFEB) was analyzed.
A rat model of IVDD was used to evaluate the in vivo efficacy of the exosomes.

Main Results

Hypoxia-induced BMSC exosomes successfully delivered BNIP3 to NPCs, improving mitochondrial quality control and reducing senescence.
BNIP3 was found to interact with ANXA2, facilitating TFEB nuclear translocation and activating autophagy/lysosomal genes.
Exosome treatment in a rat IVDD model demonstrated disc repair, delayed NPC aging, and enhanced extracellular matrix synthesis.

Conclusions

Hypoxia-induced BMSC exosomes carrying BNIP3 offer a promising therapeutic strategy for IVDD.
The BNIP3/ANXA2/TFEB signaling axis is crucial for mitigating NPC aging and promoting disc repair.
This study presents a novel exosome-based approach targeting mitochondrial dysfunction for IVDD treatment.

Keywords:

Intervertebral disc degeneration bone marrow mesenchymal stem cells exosomes hypoxia‐preconditioned mesenchymal stem cells matrix reconstruction mitophagy