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.

Objectives: Gli1⁺ cells have received extensive attention in tissue homeostasis and injury mobilization. The aim of this study was to investigate whether Gli1⁺ cells respond to force and contribute to bone remodelling.Materials and methods: We established orthodontic tooth movement (OTM) model to assess the bone response for mechanical force. The transgenic mice were utilized to label and inhibit Gli1⁺ cells, respectively. Additionally, mice that conditional ablate Yes‐associated protein (Yap) in Gli1⁺ cells were applied in the present study. The tooth movement and bone remodelling were analysed.Results: We first found Gli1⁺ cells expressed in periodontal ligament (PDL). They were proliferated and differentiated into osteoblastic cells under tensile force. Next, both pharmacological and genetic Gli1 inhibition models were utilized to confirm that inhibition of Gli1⁺ cells led to arrest of bone remodelling. Furthermore, immunofluorescence staining identified classical mechanotransduction factor Yap expressed in Gli1⁺ cells and decreased after suppression of Gli1⁺ cells. Additionally, conditional ablation of Yap gene in Gli1⁺ cells inhibited the bone remodelling as well, suggesting Gli1⁺ cells are force‐responsive cells.Conclusions: Our findings highlighted that Gli1⁺ cells in PDL directly respond to orthodontic force and further mediate bone remodelling, thus providing novel functional evidence in the mechanism of bone remodelling and first uncovering the mechanical responsive property of Gli1⁺ cells.

Background: Osteoporosis is a highly prevalent disease that causes fractures and loss of motor function. Current drugs targeted for osteoporosis often have inevitable side effects. Bone marrow mesenchymal stem cell (BMSCs)-derived apoptotic extracellular vesicles (ApoEVs) are nanoscale extracellular vesicles, which has been shown to promote bone regeneration with low immunogenicity and high biological compatibility. However, natural ApoEVs cannot inherently target bones, and are often eliminated by macrophages in the liver and spleen. Thus, our study aimed to reconstruct ApoEVs to enhance their bone-targeting capabilities and bone-promoting function and to provide a new method for osteoporosis treatment. Methods: We conjugated a bone-targeting peptide, (Asp-Ser-Ser)₆ ((DSS)₆), onto the surface of ApoEVs using standard carbodiimide chemistry with DSPE-PEG-COOH serving as the linker. The bone-targeting ability of (DSS)₆-ApoEVs was determined using an in vivo imaging system and confocal laser scanning microscopy (CLSM). We then loaded ubiquitin ligase RING finger protein146 (RNF146) into BMSCs via adenovirus transduction to obtain functional ApoEVs. The bone-promoting abilities of (DSS)₆-ApoEVs and (DSS)₆-ApoEVs^RNF146 were measured in vitro and in vivo. Results: Our study successfully synthesized bone-targeting and gained functional (DSS)₆-ApoEVs^RNF146 and found that engineered ApoEVs could promote osteogenesis in vitro and exert significant bone-targeting and osteogenesis-promoting effects to alleviate osteoporosis in a mouse model. Conclusion: To promote the bone-targeting ability of natural ApoEVs, we successfully synthesized engineered ApoEVs, (DSS)₆-ApoEVs^RNF146 and found that they could significantly promote osteogenesis and alleviate osteoporosis compared with natural ApoEVs, which holds great promise for the treatment of osteoporosis.

Objectives: The treatment of bone defects by stem cells (MSCs) has achieved limited success over the recent few decades. The emergence of exosomes provides a new strategy for bone regeneration. Here, we aimed to investigate the effect and mechanisms of exosomes combined with dental pulp stem cells (DPSCs) on bone regeneration.Materials and Methods: We isolated exosomes from stem cells from human exfoliated deciduous teeth (SHED) aggregates and evaluated the efficacy of exosomes combined with DPSCs in a cranial bone defect model. The potential mechanisms were further investigated.Results: The effect of exosomes combined with DPSCs was remarkable on bone regeneration in vivo and exosomes promoted osteogenic differentiation of DPSCs in vitro. Mechanistically, exosomes increased the expression of mitochondrial transcription factor A (TFAM) in DPSCs by transferring TFAM mRNA. Moreover, highly expressed TFAM in DPSCs enhanced glutamate metabolism and oxidative phosphorylation (OXPHOS) activity.Conclusions: Consequently, exosomes strengthened bone regeneration of DPSCs through the activation of mitochondrial aerobic metabolism. Our study provides a new potential strategy to improve DPSC‐based bone regenerative treatment.

Background: Rheumatoid arthritis (RA) is a chronic and nonspecific autoimmune disease, which leads to joint destruction and deformity. To investigate the potential of human mesenchymal stem cells (MSCs) as a new therapeutic strategy for patients with RA, we compared the therapeutic effects of bone marrow derived MSCs (BMSCs), umbilical cord derived MSCs (UCs), and stem cells derived from human exfoliated deciduous teeth (SHED) on collagen-induced arthritis (CIA) in mice. Methods: A total of 24 DBA/1 mice were infused with type II collagen to induce RA in the experimental model. MSC-treated mice were infused with UCs, BMSCs, and SHED, respectively. Bone erosion and joint destruction were measured by micro-computed tomographic (micro-CT) analysis and hematoxylin and eosin staining. The levels of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) were measured by immunohistochemistry and Enzyme-Linked Immunosorbent Assay (ELISA). Results: Systemic delivery of MSCs significantly improved the severity of the symptoms related to CIA to greater extent compared with the untreated control group. Micro-CT revealed reduced bone erosions in the metatarsophalangeal joints upon treatment with MSCs. Additionally, according to histologic evaluation, reduced synovitis and articular destruction were observed in MSC-treated groups. The levels of TNF-α and IL-1β in the serum and joints decreased with treatment by MSCs. Conclusion: Our findings suggest that systemic infusion of UCs, BMSCs, and SHED may significantly alleviate the effects of RA. The therapeutic effect of BMSCs was greater than that of SHED, while the UCs were shown to have the best therapeutic effect on CIA mice. In conclusion, compared with BMSCs and SHED, UCs may be a more suitable source of MSCs for the treatment of patients with RA.