## 3 Effects of Vitamin D\({}_{3}\) on Dental MSCs  
### Vitamin D\({}_{3}\) Metabolism in Dental MSCs  
The exact role of vitamin D\({}_{3}\) in the metabolism of MSCs is currently under investigation [37]. Earlier studies showed that MSCs' differentiation into osteoblasts is enhanced by 1,25(OH)\({}_{2}\)D\({}_{3}\)[38]. Later, it was demonstrated that osteoblastic differentiation of MSCs is also stimulated by 25(OH)D\({}_{3}\), which implies that MSCs can convert this vitamin D\({}_{3}\) form into biologically active 1,25(OH)\({}_{2}\)D\({}_{3}\)[39]. Moreover, MSCs express several proteins involved in vitamin D\({}_{3}\) metabolism: VDR, vitamin D\({}_{3}\) hydroxylases CYP27B1, CYP27A1, and CYP24A1. The data about the regulation of CYP27B1 in MSCs are limited and contradictory. There is some evidence that the expression and activity of CYP27B1 in MSCs seems to be regulated by parathyroid hormone (PTH), 1,25(OH)\({}_{2}\)D\({}_{3}\), and insulin-like growth factor I [37]. MSCs isolated from individuals with decreased serum 25(OH)D\({}_{3}\) levels, like aged or chronic kidney disease patients, exhibit impaired differentiation ability and lower CYP27B1 expression [40]. In contrast, [PERSON] et al. reported that CYP27B1 expression in primary human osteoblasts is regulated by PTH, fibroblast growth factor 23, and calcium, but not phosphate [41]. Similarly to other cell types, the expression of CYP24A1 in MSCs is strongly up-regulated by 1,25(OH)\({}_{2}\)D\({}_{3}\) and 25(OH)D\({}_{3}\)[42; 43]. [PERSON] et al. implied that there are some differences in the expression of vitamin D\({}_{3}\) metabolism in pediatric MSCs depending on the gender [43]. All proteins involved in the conversion and activation of vitamin D\({}_{3}\) responses have been detected in dental MSCs. The expression of VDR has been reported in MSCs that originated from different dental tissues [44; 45; 46; 47; 48]. The existence and functionality of CYP27B1 in dental MSCs was first reported by [PERSON] et al., who detected this enzyme in hDPCs and human dental follicle cells (hDFCs) [48]. These cells produced 1,25(OH)\({}_{2}\)D\({}_{3}\) upon stimulation with 25(OH)D\({}_{3}\), which was inhibited by cytochrome P450 inhibitor ketoconazole [48]. Later, [PERSON] et al. showed that hGFs and hPDLCs express CYP27B1 and CYP24A1 and can convert 25(OH)D\({}_{3}\) into 1,25(OH)\({}_{2}\)D\({}_{3}\)[49]. The functional effects of 25(OH)D\({}_{3}\) have been shown in hGFs and hPDLCs [45; 47], which confirms that these cells express functionally active CYP27B1. [PERSON] et al. reported that hGFs and hPDLCs also express CYP27A1, which might convert vitamin D\({}_{3}\) into 25(OH)D\({}_{3}\) via 25 hydroxylation [50]. Thus, dental MSCs seem to possess all enzymes and proteins involved in the activation and degradation of vitamin D\({}_{3}\), which implies the existence of a local vitamin D\({}_{3}\) metabolism (Figure 1). The data about the regulation of the proteins involved in the local vitamin D\({}_{3}\) metabolism in dental MSCs are scarce. The effect of vitamin D\({}_{3}\) metabolites on the expression of VDR has been investigated in various dental MSCs [44; 47; 48; 49]. The expression of VDR is increased upon stimulation with 1,25(OH)\({}_{2}\)D\({}_{3}\) or 25(OH)D\({}_{3}\) in hDPCs, but not in hDFCs [48]. [PERSON] et al. showed that VDR expression in hGFs and hPDLCs is up-regulated by both 1,25(OH)\({}_{2}\)D\({}_{3}\) and 25(OH)D\({}_{3}\)[47]. A stimulating effect of 1,25(OH)\({}_{2}\)D\({}_{3}\) on the expression of VDR in hPDLCs was reported by [PERSON] et al. [44]. The expression of VDR in hGFs and hPDLCs does not seem to be affected by inflammatory stimuli, particularly by _Porphyromonas gingivalis_ lipopolysaccharideaccharide (LPS) in hGFs and hPDLCs [49]. Only two studies were occupied with the regulation of CYP27B1 expression in dental MSCs [48; 49]. According to [PERSON] et al., CYP27B1 expression in hDPCs and hDFCs is enhanced by 25(OH)D\({}_{3}\), but not affected by 1,25(OH)\({}_{2}\)D\({}_{3}\)[48]. [PERSON] et al.