Abstract:

Craniofacial tissue regeneration remains a pivotal challenge in oral and regenerative medicine. Mesenchymal stem/stromal cells (MSCs) are central effector cells in this process, and their functions are regulated by a sophisticated, multidimensional network. This article provides a comprehensive overview of the regulatory mechanisms governing MSCs in craniofacial regeneration. We highlight the interactive roles of metabolism, epigenetics, and immunity in precisely controlling MSC stemness, lineage-specific differentiation, and immunomodulatory capabilities. Key regulatory dimensions are explored in detail. Metabolic reprogramming, such as serine one-carbon metabolism and mitochondrial dynamics under hyperosmotic stress, couples energy production with epigenetic modifications to dictate MSC fate. The gasotransmitter hydrogen sulfide (H₂S) exerts tissue-specific effects, modulating immunoregulation via the Fas/FasL axis in gingival MSCs and promoting odontogenic differentiation in dental pulp stem cells (DPSCs) via the transient receptor potential action channel subfamily vanilloid member 1 (TRPV1)/β-catenin pathway. Epigenetic mechanisms, including DNA demethylation by ten-eleven translocation (TET) enzymes and chromatin remodeling by special AT-rich sequence-binding protein 2 (SATB2), finely tune MSC homeostasis and differentiation potential. Crucially, MSCs do not function in isolation. Their bidirectional crosstalk with immune cells, mediated by exosomes and soluble factors, is essential for bone homeostasis. Mechanical overloading can trigger MSCs to promote T helper 17 (Th17) cell polarization via metabolic reprogramming, exacerbating bone destruction. Conversely, H₂S-modified exosomes from M2 macrophages can enhance MSC osteogenesis, demonstrating a synergistic metabolic-immune axis for bone regeneration. Exosomes themselves serve as versatile therapeutic carriers, capable of delivering miRNAs (e.g., miR-125a/b) or functional mitochondrial DNA to modulate immunity or repair cellular metabolism. The clinical translation of MSCs holds great promise for treating conditions like periodontitis and temporomandibular joint disorders. Advances in engineered exosomes and biomaterial carriers (e.g., hydrogels) offer strategies for targeted delivery and enhanced efficacy. Future research must focus on developing tissue-specific delivery systems, refining exosome engineering for precise cargo loading, and leveraging multi-omics technologies to decipher the complex stem cell niche. This progression from empi-rical application to rationally designed, precision therapies will be critical for addressing clinical challenges in craniofacial reconstruction.

Key words: Mesenchymal stem cells, Regeneration, Tissue engineering, Skull, Facial bones