Periodontal ligament stem cells ameliorate experimental colitis by restoring macrophage mitochondrial homeostasis associated with PINK1/Parkin-related mitochondrial quality control.

Inflammatory bowel disease (IBD) is characterized by persistent mucosal inflammation and dysregulated macrophage responses, in which mitochondrial dysfunction reinforces inflammatory activation. Periodontal ligament stem cells (PDLSCs) possess immunomodulatory potential, but whether they regulate macrophage inflammation by restoring mitochondrial homeostasis in colitis remains unclear. Here, human PDLSCs were indirectly co-cultured with lipopolysaccharide-stimulated THP-1-derived macrophages, and their therapeutic effects were further examined in dextran sulfate sodium (DSS)-induced colitis mice. PDLSCs suppressed macrophage pro-inflammatory activation while enhancing anti-inflammatory mediator expression. RNA sequencing combined with MitoCarta3.0 analysis revealed that PDLSC-regulated genes were enriched in mitochondrial function, mitophagy, oxidative stress, ferroptosis, and metabolic adaptation pathways. Mechanistically, PDLSCs alleviated mitochondrial ultrastructural injury, restored mtTFA expression and mitochondrial membrane potential, enhanced respiratory chain complex I/III activity and ATP production, and attenuated intracellular and mitochondrial oxidant-sensitive signals. PDLSCs also decreased OMA1 and Drp-1, restored OPA1 and Mfn1, and promoted PINK1-Parkin signaling, whereas Mdivi-1 attenuated their anti-inflammatory effects. In vivo imaging revealed PDLSC-associated fluorescence in the inflamed colon, and PDLSC treatment mitigated DSS-induced weight loss, disease activity, colonic shortening, MPO activation, histological injury, mucus barrier disruption, and collagen deposition. PDLSC treatment also suppressed M1-associated macrophage activation while promoting M2-associated macrophage polarization, preserved mitochondrial ultrastructure, improved mitochondrial respiratory function and ATP generation, and restored the expression of PINK1 and Parkin in colonic tissue. In conclusion, PDLSCs ameliorate experimental colitis by reshaping macrophage inflammatory responses and restoring mitochondrial quality control, with potential involvement of PINK1/Parkin-associated mitophagy.