Intercellular mitochondrial transfer alleviates pyroptosis in dental pulp damage

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-alpha secreted from pyroptotic odontoblasts activates NF-kappa B signalling in BMSCs via the paracrine pathway, thereby promoting the TNT formation in BMSCs and enhancing mitochondrial transfer efficiency. Inhibitions of NF-kappa B signalling and TNF-alpha 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.

Automated summary

Mitochondrial transfer has shown potential as a therapeutic strategy for tissue repair, but its role in protecting against pulpitis is unclear. This study found that hyperactivated NLRP3 inflammasomes and pyroptosis were present in pulpitis tissues, particularly in the odontoblast layer, and mitochondrial oxidative stress played a role in driving this pathology. Bone marrow mesenchymal stem cells (BMSCs) were found to donate their mitochondria to odontoblasts via tunnelling nanotubes (TNTs), reducing mitochondrial oxidative stress and pyroptosis. The transfer efficiency was enhanced by TNF-alpha secretion from pyroptotic odontoblasts, activating NF-kappa B signaling in BMSCs and promoting TNT formation.