Melatonin regulation and the function of the periodontal ligament: Future perspective and challenges
Periodontal research is undergoing an exciting transition with the emergence of new technologies and molecules that are revolutionizing traditional therapeutic strategies. In particular, the recent focus on the use of human periodontal ligament stem cells (PDLSCs) and the regenerative potential of melatonin (MT) has sparked discussions on how to antagonize cellular aging and enhance periodontal tissue regeneration. Recently published research provides a detailed analysis of how MT delays PDLSC senescence and enhances their regenerative capacity, offering new perspectives for the treatment of periodontal disease. Rather than providing definitive answers, this research encourages readers to reflect on current challenges and future opportunities in the field. Clinical evidence and future challenges PDLSCs represent a promising resource for oral tissue regeneration due to their self-renewal and multidirectional differentiation capabilities[ - ]. However, cellular aging and oxidative stress, exacerbated by the extension of the human lifespan and the growing elderly population, represent significant obstacles. The aging microenvironment and oxidative stress inhibit the regenerative capacity of PDLSCs, reducing their vitality and efficacy in tissue regeneration therapies. In addition, mesenchymal stem cells undergo mitotic arrest, replicative senescence, and changes in stemness over time, limiting their clinical potential. In the context of regenerative therapy research, MT has emerged as a molecule of great interest (Table ). In addition to being a potent endogenous antioxidant, MT can regulate mesenchymal stem cell proliferation, apoptosis, and properties, thereby helping to counteract the effects of oxidative stress. Recent research demonstrated that MT not only reduces the levels of reactive oxygen species in PDLSCs, but also restores their normal morphology and enhances both proliferation and osteogenic differentiation potential. These findings open new avenues for using MT as a tool to delay cellular aging and enhance periodontal regeneration. A key aspect is the focus on the Hippo-Yes-associated protein (YAP) signaling pathway, a fundamental system to maintain stem cell properties and regulate cell growth. YAP, a key effector protein of the Hippo pathway, has been identified as a critical mediator of the PDLSC response to oxidative stress. Under stress conditions, YAP expression is significantly reduced, but MT administration restores YAP levels, promoting the maintenance of PDLSC stemness. This mechanism provides new insights into how MT may counteract cellular aging and enhance tissue regeneration. With an aging population and an increase in age-related diseases, regenerative research is becoming increasingly important. The ability to delay the aging process of PDLSCs could be a game changer in the treatment of periodontal disease, which affects a significant proportion of the world’s population. This study not only provides new evidence for the use of MT, but also highlights the need to develop therapeutic strategies that effectively address the limitations imposed by oxidative stress and cellular aging. In addition to MT-based therapies, another rapidly expanding area of research is the use of probiotics to improve oral microbiota balance and promote tissue regeneration. By modulating inflammation and promoting a healthy microbial environment, probiotics may provide an additional tool to enhance the efficacy of preventive and regenerative therapies. The combination of pharmacological and biological approaches, such as the use of MT and probiotics, may represent a new frontier in regenerative periodontology. 

PDLSCs represent a promising resource for oral tissue regeneration due to their self-renewal and multidirectional differentiation capabilities[ - ]. However, cellular aging and oxidative stress, exacerbated by the extension of the human lifespan and the growing elderly population, represent significant obstacles. The aging microenvironment and oxidative stress inhibit the regenerative capacity of PDLSCs, reducing their vitality and efficacy in tissue regeneration therapies. In addition, mesenchymal stem cells undergo mitotic arrest, replicative senescence, and changes in stemness over time, limiting their clinical potential. In the context of regenerative therapy research, MT has emerged as a molecule of great interest (Table ). In addition to being a potent endogenous antioxidant, MT can regulate mesenchymal stem cell proliferation, apoptosis, and properties, thereby helping to counteract the effects of oxidative stress. Recent research demonstrated that MT not only reduces the levels of reactive oxygen species in PDLSCs, but also restores their normal morphology and enhances both proliferation and osteogenic differentiation potential. These findings open new avenues for using MT as a tool to delay cellular aging and enhance periodontal regeneration. A key aspect is the focus on the Hippo-Yes-associated protein (YAP) signaling pathway, a fundamental system to maintain stem cell properties and regulate cell growth. YAP, a key effector protein of the Hippo pathway, has been identified as a critical mediator of the PDLSC response to oxidative stress. Under stress conditions, YAP expression is significantly reduced, but MT administration restores YAP levels, promoting the maintenance of PDLSC stemness. This mechanism provides new insights into how MT may counteract cellular aging and enhance tissue regeneration. With an aging population and an increase in age-related diseases, regenerative research is becoming increasingly important. The ability to delay the aging process of PDLSCs could be a game changer in the treatment of periodontal disease, which affects a significant proportion of the world’s population. This study not only provides new evidence for the use of MT, but also highlights the need to develop therapeutic strategies that effectively address the limitations imposed by oxidative stress and cellular aging. In addition to MT-based therapies, another rapidly expanding area of research is the use of probiotics to improve oral microbiota balance and promote tissue regeneration. By modulating inflammation and promoting a healthy microbial environment, probiotics may provide an additional tool to enhance the efficacy of preventive and regenerative therapies. The combination of pharmacological and biological approaches, such as the use of MT and probiotics, may represent a new frontier in regenerative periodontology. 

The article discussed here represents not only a significant contribution to the scientific literature but also a starting point for broader reflections. The integration of new molecules, such as MT, with advancements in periodontal tissue regeneration offers a landscape rich in potential, but also in challenges. The effects of MT on the Hippo-YAP pathway and its role in maintaining PDLSC stemness are only one piece of a complex puzzle that deserves further study. In the future, it will be important to explore how these findings can be translated into practical clinical applications, while encouraging critical reflection on new therapeutic approaches. It will be interesting to see how periodontal research develops and what new solutions may emerge in the treatment of diseases associated with aging and cellular decline. 

