2. Academic Validation
  3. cGAMP-targeting injectable hydrogel system promotes periodontal restoration by alleviating cGAS-STING pathway activation

cGAMP-targeting injectable hydrogel system promotes periodontal restoration by alleviating cGAS-STING pathway activation

  • Bioact Mater. 2025 Feb 13:48:55-70. doi: 10.1016/j.bioactmat.2025.02.010.
Xiang Liu 1 2 3,  Hua Zhang 4,  Lei Xu 1 2,  Huayu Ye 1 2,  Jinghuan Huang 5,  Jing Xiang 1 2,  Yunying He 1 2,  Huan Zhou 6,  Lingli Fang 1 2,  Yunyan Zhang 1 2,  Xuerong Xiang 1 2,  Richard D Cannon 7,  Ping Ji 1 2,  Qiming Zhai 1 2
Affiliations

Affiliations

  • 1 College of Stomatology, Chongqing Medical University, Chongqing, China.
  • 2 Chongqing Key Laboratory of Oral Diseases, Chongqing, China.
  • 3 Department of Stomatology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 4 Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Orthopedic Department of Shanghai Sixth People's Hospital, Shanghai, China.
  • 6 Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
  • 7 Department of Oral Sciences, Sir John Walsh Research Institute, Dentistry, University of Otago, Dunedin, 9054, New Zealand.
PMID: 40303968 DOI: 10.1016/j.bioactmat.2025.02.010
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.

Keywords

Inflammatory environment; Injectable hydrogel system; Osteogenic differentiation; Periodontal ligament stem cells; cGAMP homeostasis; cGAS-STING pathway.

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