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Updated: May 25, 2025
Mesenchymal Stem Cell Regulation of Macrophage Phagocytosis; Quantitation and Imaging
Published on: July 16, 2021
MSCs-EVs harboring OA immune memory reprogram macrophage phenotype via modulation of the mt-ND3/NADH-CoQ axis for OA
Jingdi Zhan1,2, Jing Zou1,2, Qiming Pang1,2
1Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Background:
Osteoarthritis (OA) is a prevalent degenerative joint disease and current therapies are insufficient to halt its progression. Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) offer promising therapeutic potential for OA treatment, and their efficacy can be enhanced through strategic engineering approaches.
Methods:
Inspired by the immune memory of the adaptive immune system, we developed an engineered strategy to impart OA-specific immune memory to MSCs-EVs. Using Luminex technology, inflammatory factors (IFN-γ, IL-6, and TNF-α), which mimic the OA inflammatory microenvironment, were identified and used to prime MSCs, generating immune memory-bearing MSCs-EVs (iEVs). Proteomic analysis and complementary experiments were conducted to evaluate iEVs' effects on macrophage phenotypic reprogramming.
Results:
iEVs, particularly IL-6-EV, exhibited potent immunoregulatory functions along with the ability to modulate mitochondrial metabolism. Both in vitro and in vivo, IL-6-EV significantly reprogrammed macrophages towards the M2 subtype, effectively suppressing articular inflammation and OA progression. Mechanistic studies revealed that IL-6-EV facilitated M2 polarization by regulating mitochondrial oxidative phosphorylation via the mt-ND3/NADH-CoQ axis.
Conclusion:
This study introduces a strategy to enhance MSCs-EVs' therapeutic efficacy in OA. Multi-omics analysis and biological validation demonstrate its potential, providing new insights for MSCs-EVs' future application in OA and other clinical conditions.
Insights
Engineered mesenchymal stem cell-derived extracellular vesicles (MSCs-EVs) with immune memory effectively reprogram macrophages, suppressing osteoarthritis (OA) progression. This novel approach enhances MSC-EVs
Area of Science:
- Biomedical Engineering
- Immunology
- Regenerative Medicine
Background:
- Osteoarthritis (OA) is a widespread degenerative joint disease with limited effective therapies.
- Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) show promise for OA treatment.
- Engineering MSCs-EVs can enhance their therapeutic efficacy for OA.
Purpose of the Study:
- To engineer MSCs-EVs with OA-specific immune memory for enhanced therapeutic potential.
- To investigate the immunoregulatory and metabolic effects of engineered EVs on macrophages.
Main Methods:
- Identified key inflammatory factors (IFN-γ, IL-6, TNF-α) in the OA microenvironment using Luminex technology.
- Primed MSCs with these factors to generate immune memory-bearing MSCs-EVs (iEVs).
- Evaluated iEVs' effects on macrophage reprogramming via proteomic analysis and in vitro/in vivo experiments.
Main Results:
- Engineered EVs (iEVs), particularly IL-6-EV, demonstrated potent immunoregulatory functions.
- IL-6-EV significantly reprogrammed macrophages to the M2 subtype, suppressing inflammation and OA progression.
- Mechanistic studies revealed IL-6-EV regulates M2 polarization via the mt-ND3/NADH-CoQ mitochondrial axis.
Conclusions:
- A novel strategy was developed to enhance MSC-EVs' therapeutic efficacy for osteoarthritis.
- Multi-omics analysis and biological validation support the potential of engineered EVs.
- This approach offers new insights for MSC-EV applications in OA and other conditions.
