State 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.
Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Adv Sci (Weinh). 2022 Feb;9(4):e2103839. doi: 10.1002/advs.202103839. Epub 2021 Dec 11.
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 Ca 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 Ca 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.
组织特异性间充质干细胞（MSCs）中线粒体功能障碍在细胞命运和慢性炎症相关骨病（如牙周炎和骨关节炎）的发病机制中起着关键作用。然而，目前仍然没有有效的方法通过生理恢复线粒体和 MSCs 的功能来治疗慢性炎症相关的骨病。在这里，首先发现慢性炎症会导致内质网中过多的 Ca 转移到线粒体，从而导致线粒体钙超载，进一步损伤线粒体。此外，在慢性炎症条件下，由于自噬体激活 Wnt/β-catenin 通路抑制了线粒体自噬，受损的线粒体在 MSCs 中不断积累，损害了 MSCs 的分化。基于这一机制发现，制备了细胞内微环境（酯酶和低 pH）响应型纳米颗粒，以捕获 MSCs 中线粒体周围的 Ca，从而调节 MSC 线粒体钙流，对抗线粒体功能障碍。此外，相同的纳米颗粒能够将 siRNA 递送至 MSCs，抑制 Wnt/β-catenin 通路并调节原本功能失调的线粒体的自噬。这些经过精密设计的纳米颗粒被称为“纳米修复器”，可生理性地恢复线粒体和 MSCs 的功能，从而有效治疗牙周炎和骨关节炎。该概念可能通过线粒体质量控制干预扩展到其他疾病的治疗。
