The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Department of Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Cell Prolif. 2023 Sep;56(9):e13442. doi: 10.1111/cpr.13442. Epub 2023 Apr 21.
Mitochondrial transfer is emerging as a promising therapeutic strategy for tissue repair, but whether it protects against pulpitis remains unclear. Here, we show that hyperactivated nucleotide-binding domain and leucine-rich repeat protein3 (NLRP3) inflammasomes with pyroptotic cell death was present in pulpitis tissues, especially in the odontoblast layer, and mitochondrial oxidative stress (OS) was involved in driving this NLRP3 inflammasome-induced pathology. Using bone marrow mesenchymal stem cells (BMSCs) as mitochondrial donor cells, we demonstrated that BMSCs could donate their mitochondria to odontoblasts via tunnelling nanotubes (TNTs) and, thus, reduce mitochondrial OS and the consequent NLRP3 inflammasome-induced pyroptosis in odontoblasts. These protective effects of BMSCs were mostly blocked by inhibitors of the mitochondrial function or TNT formation. In terms of the mechanism of action, TNF-α secreted from pyroptotic odontoblasts activates NF-κB signalling in BMSCs via the paracrine pathway, thereby promoting the TNT formation in BMSCs and enhancing mitochondrial transfer efficiency. Inhibitions of NF-κB signalling and TNF-α secretion in BMSCs suppressed their mitochondrial donation capacity and TNT formation. Collectively, these findings demonstrated that TNT-mediated mitochondrial transfer is a potential protective mechanism of BMSCs under stress conditions, suggesting a new therapeutic strategy of mitochondrial transfer for dental pulp repair.
线粒体转移作为一种有前途的组织修复治疗策略正在出现，但它是否能预防牙髓炎尚不清楚。在这里，我们表明，牙髓组织中存在高激活核苷酸结合域和富含亮氨酸重复蛋白 3（NLRP3）炎症小体伴细胞焦亡，特别是在成牙本质细胞层，线粒体氧化应激（OS）参与驱动这种 NLRP3 炎症小体诱导的病理。我们使用骨髓间充质干细胞（BMSCs）作为线粒体供体细胞，证明 BMSCs 可以通过隧道纳米管（TNTs）将其线粒体转移给成牙本质细胞，从而减轻成牙本质细胞的线粒体 OS 和随之而来的 NLRP3 炎症小体诱导的细胞焦亡。BMSCs 的这些保护作用大多被线粒体功能或 TNT 形成抑制剂所阻断。就作用机制而言，来自焦亡的成牙本质细胞的 TNF-α通过旁分泌途径激活 BMSCs 中的 NF-κB 信号通路，从而促进 BMSCs 中 TNT 的形成，并增强线粒体转移效率。BMSCs 中 NF-κB 信号通路和 TNF-α分泌的抑制抑制了它们的线粒体供体能力和 TNT 形成。总之，这些发现表明，TNT 介导的线粒体转移是 BMSCs 在应激条件下的一种潜在保护机制，为牙髓修复的线粒体转移提供了一种新的治疗策略。
