The present article reviews the emerging role of melatonin (MT) and the Hippo-Yes-associated protein signaling pathway in periodontal regeneration, highlighting their potential to delay the aging process of periodontal ligament stem cells (PDLSCs). Oxidative stress and cellular senescence are major obstacles in regenerative therapies, especially in an aging population. MT, a potent antioxidant, restores the morphology, proliferation, and osteogenic differentiation potential of PDLSCs under oxidative stress conditions. Recent research highlights how MT enhances PDLSC stemness by upregulating Yes-associated protein expression, offering a promising therapeutic strategy to antagonize tissue degeneration. In addition, the article discusses the growing interest in probiotics as a complementary approach to improve oral microbiota and support tissue regeneration. The integration of MT with traditional and novel therapeutic approaches may pave the way for innovative preventive or active treatments in periodontology, aimed at reducing oxidative stress. Future research needs to focus on translating these findings into clinical applications and promoting a deeper understanding of periodontal regeneration and cellular aging.

The teeth are vertebrate-specific, highly specialized organs performing fundamental functions of mastication and speech, the maintenance of which is crucial for orofacial homeostasis and is further linked to systemic health and human psychosocial well-being. However, with limited ability for self-repair, the teeth can often be impaired by traumatic, inflammatory, and progressive insults, leading to high prevalence of tooth loss and defects worldwide. Regenerative medicine holds the promise to achieve physiological restoration of lost or damaged organs, and in particular an evolving framework of developmental engineering has pioneered functional tooth regeneration by harnessing the odontogenic program. As a key event of tooth morphogenesis, mesenchymal condensation dictates dental tissue formation and patterning through cellular self-organization and signaling interaction with the epithelium, which provides a representative to decipher organogenetic mechanisms and can be leveraged for regenerative purposes. In this review, we summarize how mesenchymal condensation spatiotemporally assembles from dental stem cells (DSCs) and sequentially mediates tooth development. We highlight condensation-mimetic engineering efforts and mechanisms based on ex vivo aggregation of DSCs, which have achieved functionally robust and physiologically relevant tooth regeneration after implantation in animals and in humans. The discussion of this aspect will add to the knowledge of development-inspired tissue engineering strategies and will offer benefits to propel clinical organ regeneration.