## 3 Undifferentiated Cells (Stem Cells)
### Adult Stem Cells
#### 3.4.4 Applications in BTE  
The use of DPSCs for BTE applications has been widely investigated in recent years. These cells express osteogenic commitment markers (e.g., BGLAP, Oso, and OP) and can produce bone-like nodule formation in vitro [308]. As recently reviewed by [PERSON] et al., DPSCs are a valuable cell source for bone repair and regeneration strategies when they are applied together with suitable natural and synthetic scaffolds [309]. For example, [PERSON] et al. grafted DPSCs with collagen sponge complexes in order to regenerate human mandible bone defect [310]. The results revealed that the alveolar bone had optimal vertical repair and complete restoration of periodontal tissue after three months of grafting. In addition, histological observations demonstrated the complete regeneration of bone at the injury site at one-year post-grafting. More studies have focused on the use of these cells with synthetic scaffolds, especially those made of tricalcium phosphate [311; 312]. The in vitro and in vivo osteogenic differentiations of SHEDs were also identified in various experimental studies [313; 314; 315]. A high proliferation rate and a less invasive procedure for obtaining SHEDs are considered beneficial in comparison with BM-MSCs. Moreover, it has been reported that SHEDs have a higher proliferation rate and differentiation ability in vitro, as well as a higher mineralization potential in vivo compared to the DPSCs [291]. However, there are other studies reporting a lack of significant differences among the cells mentioned above regarding bone regeneration capacity. As an illustration, [PERSON] et al. compared the bone regeneration ability among human SHEDs, DPSCs, and BM-MSCs in vivo [316]. The authors transplanted all three types of stem cells with a poly(lactic-co-glycolic acid) (PLGA) barrier membrane as a scaffold for reconstruction of a critical-sized bone defect in the calvaria of immuno-deficient mice. The results showed that there was no significant difference among different groups in terms of bone regeneration after 12 weeks of implantation. However, the largest osteoid and widely distributed collagen fibers were observed in the animals treated with SHEDs/scaffolds as compared to other groups. The authors concluded that SHEDs could be used as one of the best cell sources for the reconstruction of the alveolar cleft. However, there are some disadvantages regarding the use of SHEDs in BTE applications such as the need to extract healthy teeth in order to isolate and harvest the MSCs. As another stem cell source in the teeth, PDLSCs can give rise to the osteogenic lineages in vitro and in vivo. In 2010, [PERSON] et al. compared the in vitro osteogenesis potential between PDLSCs and SHEDs [317]. The authors cultured both cell types in a medium containing retinoic acid (RA) and dexamethasone (Dex) for 21 days. Their results revealed that RA and Dex have inhibitory effects on the proliferation of SHEDs and PDLSCs. However, RA could significantly up-regulate the gene expression of osteogenic markers like ALP in both cell types. This effect was increased after adding insulin to the culture medium. Although, RA+ insulin treatment had better effects on the proliferation of PDLSCs and, thereby, led to greater calcium deposition at three weeks post-incubation. The authors concluded that PDLSCs are a better osteogenic stem cell source than SHEDs. This ability along with the immunomodulatory properties offers PDLSCs as good alternatives to BM-MSCs in BTE applications [318; 319]. Similar to other cells, the genetic engineering of this type of stem cell via the insertion and subsequent up-regulation of genes involved in osteogenesis (e.g., BMP2) may improve their potency in terms of in vivo bone reconstruction [320; 321]. [PERSON] et al. in 2014 compared the potential of PDLSCs versus BM-MSCs in combination with Bio-Oss\({}^{\circledR}\) commercial scaffolds for ectopic and in situ bone formation [322].