Abstract
The impaired function of periodontal ligament stem cells (PDLSCs) impedes restoration of periodontal tissues. The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA (dsDNA), but its role in regulating the function of PDLSCs is still unclear. In this study, we found that mitochondrial DNA (mtDNA) was released into the cytoplasm through the mitochondrial permeability transition pore (mPTP) in PDLSCs upon inflammation, which binds to cGAS and activated the STING pathway by promoting the production of cGAMP, and ultimately impaired the osteogenic differentiation of PDLSCs. Additionally, it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1 (ABCC1, a cGAMP exocellular transporter) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1, a cGAMP hydrolase), which further aggravated the accumulation of intracellular cGAMP, leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs. Furthermore, we designed a hydrogel system loaded with a mPTP blocker, an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production, exocytosis, and clearance of cGAMP. In conclusion, our results highlight the profound effects, and specific mechanisms, of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.
• The cGAS-STING pathway activation hinders the osteogenic differentiation of PDLSCs, consequently impeding the restoration of periodontal tissue.
• Inflammation facilitates the accumulation of cGAMP by enhancing its synthesis and inhibiting its extracellular export and degradation, thereby contributing to the sustained activation of the cGAS-STING pathway in PDLSCs.
• A hydrogel system designed to restore the homeostasis of cGAMP, loaded with mPTP blockers to inhibit mtDNA release, an ABCC1 agonist to promote extracelluar cGAMP transport and ENPP1 to degrade cGAMP, has the potential to effectively promote periodontal tissue regeneration.