## 6 Future Perspectives and Open Questions  
The existing literature suggests that the functional properties of dental MSCs are affected by different vitamin D\({}_{3}\) metabolites (Figure 2). Furthermore, dental MSCs express the enzymes, which enable the conversion of vitamin D\({}_{3}\) into 25(OH)D\({}_{3}\) and subsequently to 1,25(OH)\({}_{2}\)D\({}_{3}\), as well as 1,25(OH)\({}_{2}\)D\({}_{3}\) inactivating enzyme. This suggests the existence of a local vitamin D\({}_{3}\) metabolism in various dental tissues. The conversion of vitamin D\({}_{3}\) by dental MSCs is assumed to be important in the local tissue homeostasis, although its exact role has still to be investigated. One of the most important questions is the regulation of local vitamin D\({}_{3}\) conversion by dental MSCs, which remains largely unexplored. Obviously, CYP27B1 is differently regulated in dental tissues than in the kidneys. Another critical question is the physiological relevance of 24R,25(OH)\({}_{2}\)D\({}_{3}\): It is known that this metabolite possesses biological activity, but its effects in dental MSCs are not known so far. Understanding of the local vitamin D\({}_{3}\) metabolism could open new perspectives in the treatment of periodontal disease. Vitamin D\({}_{3}\) deficiency is a recognized risk factor of periodontal disease. However, the effect of vitamin D\({}_{3}\) supplementation during periodontal therapy is almost not explored. It should be noted that an effective increase in the serum 25(OH)D\({}_{3}\) within a short time could be achieved only by high doses of vitamin D\({}_{3}\) supplementation. Mainly, supplementation with 1000 IU (25 \(\upmu\)g) during 3-4 months is necessary to enhance the serum level of 25(OH)D\({}_{3}\) by 10 ng/mL [118]. Moreover, an increase in 25(OH)D\({}_{3}\) by vitamin D\({}_{3}\) supplementation does not always result in a clinically relevant effect [119; 120]. High doses of vitamin D\({}_{3}\) might have a potentially harmful impact on bone fracture [121; 122]. Therefore, further randomized clinical trials are necessary to determine the doses of vitamin D\({}_{3}\) supplements during periodontal therapy based on the balance of clinical effectiveness and safety [123; 124]. Approaches for local vitamin D\({}_{3}\) delivery should be elaborated as an addendum for the dietary supplementation, and their therapeutic and regenerative potential should be tested in pre-clinical and clinical studies. Modern cell-based therapy is based on three pillars: Cells, scaffold, and growth factors [125; 126; 127]. Vitamin D\({}_{3}\)-loaded scaffolds could be considered as potential carriers for local vitamin D\({}_{3}\) delivery [128] and this approach should be tested in the dental field. [PERSON] et al. reported that 1,25(OH)\({}_{2}\)D\({}_{3}\) enhances the expression of integrin \(\alpha\)V and integrin \(\beta\)3 in human dental bud cells [61]. Integrins are transmembrane proteins mediating cell interaction with extracellular matrix and scaffolds and might facilitate dental tissue regeneration [129]. Thus, vitamin D\({}_{3}\) might modify the interaction of dental MSCs with a scaffold, but this question needs to be further investigated. Modern scaffolds are characterized by unique structural features of both micro- and nanoscale levels. Nanostructure features of scaffolds are known to influence cell response [130] and might hypothetically modulate vitamin D\({}_{3}\) biological activity. Furthermore, modulation of the expression and activity of the proteins involved in the local vitamin D\({}_{3}\) metabolism could also be considered as a potential therapeutic strategy. However, the mechanisms involved in the regulation of the local vitamin D\({}_{3}\) homeostasis in dental tissues need to be further explored. An interesting perspective is the adjustment of the local vitamin D\({}_{3}\) homeostasis by optimizing environmental factors, such as lifestyle and food intake [131]. Some dietary supplements like docosahexaenoicenoic acid and curcumin are low-affinity VDR ligands [132].