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Nanorepairers Rescue Inflammation-Induced Mitochondrial Dysfunction in Mesenchymal Stem Cells
Qiming Zhai1,2, Xin Chen3, Dongdong Fei1
1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Abstract:
Mitochondrial dysfunction in tissue-specific mesenchymal stem cells (MSCs) plays a critical role in cell fate and the morbidity of chronic inflammation-associated bone diseases, such as periodontitis and osteoarthritis. However, there is still no effective method to cure chronic inflammation-associated bone diseases by physiologically restoring the function of mitochondria and MSCs. Herein, it is first found that chronic inflammation leads to excess Ca2+ transfer from the endoplasmic reticulum to mitochondria, which causes mitochondrial calcium overload and further damage to mitochondria. Furthermore, damaged mitochondria continuously accumulate in MSCs due to the inhibition of mitophagy by activating the Wnt/β-catenin pathway under chronic inflammatory conditions, impairing the differentiation of MSCs. Based on the mechanistic discovery, intracellular microenvironment (esterase and low pH)-responsive nanoparticles are fabricated to capture Ca2+ around mitochondria in MSCs to regulate MSC mitochondrial calcium flux against mitochondrial dysfunction. Furthermore, the same nanoparticles are able to deliver siRNA to MSCs to inhibit the Wnt/β-catenin pathway and regulate mitophagy of the originally dysfunctional mitochondria. These precision-engineered nanoparticles, referred to as "nanorepairers," physiologically restore the function of mitochondria and MSCs, resulting in effective therapy for periodontitis and osteoarthritis. The concept can potentially be expanded to the treatment of other diseases via mitochondrial quality control intervention.
Insights
New nanorepairers restore mitochondrial function in mesenchymal stem cells (MSCs) for treating inflammatory bone diseases like periodontitis and osteoarthritis by regulating calcium and mitophagy.
Area of Science:
- Biomedical Engineering
- Cell Biology
- Regenerative Medicine
Background:
- Mitochondrial dysfunction in mesenchymal stem cells (MSCs) contributes to chronic inflammatory bone diseases.
- Current treatments lack methods to physiologically restore MSC and mitochondrial function.
Purpose of the Study:
- To elucidate the mechanisms of mitochondrial dysfunction in MSCs under chronic inflammation.
- To develop a novel therapeutic strategy for periodontitis and osteoarthritis by targeting mitochondrial quality control.
Main Methods:
- Investigated chronic inflammation-induced Ca2+ overload and mitophagy inhibition in MSCs via Wnt/β-catenin pathway.
- Fabricated intracellular microenvironment-responsive nanoparticles delivering Ca2+ chelators and siRNA.
- Administered nanoparticles to capture Ca2+ and inhibit Wnt/β-catenin, restoring mitophagy and MSC function.
Main Results:
- Chronic inflammation causes ER-to-mitochondria Ca2+ overload and impaired mitophagy in MSCs.
- Nanoparticles successfully captured excess Ca2+ and delivered siRNA to inhibit Wnt/β-catenin.
- Restored mitochondrial function and MSC differentiation, leading to effective treatment of periodontitis and osteoarthritis.
Conclusions:
- Mechanistic insights into MSC mitochondrial dysfunction provide a basis for targeted therapy.
- Precision-engineered nanorepairers offer a novel approach to physiologically restore mitochondrial and MSC function.
- This strategy holds potential for treating various diseases through mitochondrial quality control intervention.
