Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 5, Issue 1, Pages 20-32Publisher
WILEY
DOI: 10.5966/sctm.2015-0163
Keywords
Periodontal ligament stem cells; Lipoxin A(4); Immunomodulation; Lipid mediators; Regeneration
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Funding
- Cari-Chieti Foundation (Italy)
- Italian Ministry of Education, University and Research [PRIN 2010YK7Z5K_002, PRIN 20102ZLNJ5, FIRB RBAP1047J_006]
- NIH [GM-095467]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P01GM095467] Funding Source: NIH RePORTER
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Unresolved inflammation and tissue destruction are underlying mechanisms of periodontitis, which is linked to dysregulated polymorphonuclear neutrophil (PMN) functions. Lipoxin A(4) (LXA(4)) is a specialized proresolving lipid mediator (SPM) that dampens excessive inflammation, promotes resolution, and protects from leukocyte-mediated tissue damage. Human periodontal ligament stem cells (hPDLSCs) represent key players during tissue regeneration and may contribute to resolution of inflammation; thus, they may represent a promising tool in regenerative dentistry. In the present study, we investigated the actions of hPDLSCs on PMN apoptosis and antimicrobial functions, and determined the impact of LXA(4) on hPDLSCs. hPDLSCs significantly reduced apoptosis and stimulated microbicidal activity of human PMNs, via both cell-cell interactions and paracrine mechanisms. Lipid mediator metabololipidomics analysis demonstrated that hPDLSCs biosynthesize SPMs, including resoivin D1, D2, D5, and D6; protectin D1; maresins; and LXB4; as well as prostaglandins D-2, E-2, and F-2 alpha. LXA4 significantly enhanced proliferation, migration, and wound healing capacity of hPDLSCs through the activation of its cognate receptor ALX/FPR2, expressed on hPDLSCs. Together, these results demonstrate that hPDLSCs modulate PMN functions, and provide the first evidence that stem cells generate SPM and that the LXA(4)-ALX/FPR2 axis regulates regenerative functions of hPDLSCs by a novel receptor-mediated mechanism.
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