Cellular senescence in craniofacial tissue regeneration:inducers, biomarkers, and interventions.

Craniofacial defects and dental tissue loss have significant negative impacts on the structure and function of jaws and face, often resulting in psychological issues in patients, emphasizing the urgent need for effective craniofacial tissue reconstruction. Unfortunately, natural regeneration of these tissues is limited. Dental-derived mesenchymal stem cells (MSCs) have emerged as a promising resource for tissue engineering-based therapeutic approaches. However, the clinical outcomes of MSC-based transplantation have not met expectations due to various complex reasons, and cellular senescence is recognized as one of the potential mechanisms contributing to the suboptimal results. The quality of MSC decreases during large-scale in vitro expansion, and it is also influenced by the age and the health status of donors. To address these challenges, extensive efforts have been made to developing strategies to combat senescence in tissue engineering, leveraging on current knowledge of underlying mechanisms. This review aims to elucidate the impact of cell senescence in craniofacial and dental regeneration, and provides an overview of state-of-the-art anti-senescence strategies. We first discuss the potential factors that trigger cell senescence in craniofacial tissue engineering. Then we describe senescence biomarkers, monitoring methods for senescent MSCs, and their underlying molecular mechanisms. The primary focus of this review is on current strategies to inhibit and alleviate cell senescence in tissue engineering. We summarize the strategies concerning the prevention of cell senescence, senolysis, modulation of the senescent associated secretory phenotype (SASP), and reversal of senescent MSCs, offering promising opportunities to overcome the challenges associated with cell senescence in craniofacial tissue engineering.