# Different Approaches to the Regeneration of Dental Tissues in Regenerative Endodontics
## 1 Introduction
* Dental follicle precursor cells (DFPCs): Localized in a dental sac, also known as a dental follicle, a loose connective tissue that surrounds developing teeth, and also impacted teeth. The latter are usually extracted and disposed of, therefore there are no controversial ethical issues linked to the sourcing of DFPCs [25]. Some studies have shown that DFPCs can transform into fibroblasts, osteoblasts, periodontal ligament, and cementoblasts [26], thus these cells may be useful in regeneration therapies of periodontal tissues [5]. Tissue regeneration requires the appropriate signals (growth and differentiating factors) that activate these cells [27]. Growth factors are extracellular proteins or polypeptides, which interact with specific-cell receptors to activate intracellular signaling cascades, eventuating in cell proliferation, differentiation, migration, and the apoptosis of numerous different cell types, including dental pulp cells and stem cells [28]. Growth factors differ in their functions, thus they may be used in many biomedical applications. Stimulation of cellular division and differentiation are coordinated by several growth factors, such as fibroblast growth factors (FGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like factor (IGF) [28]. Others are known as wound-healing promoting factors, as in the case of TGF-8 superfamily-types 1, 2, and 3 [29]. Most of these bioactive molecules are also released by odontoblast cells and fixed in the dentin matrix during tooth morphogenesis [30]. Scientific research has revealed that growth factors like PDGF, TGF, IGF-1, EGF, and FGF may participate in dentin regeneration processes when damage occurs [31], furthermore, the important role of these signaling molecules in stem cell maintenance and their contribution to dental tissues regeneration was considered. Moreover, two distinct families of growth factors, crucial for tooth formation and regeneration, are vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP) [32; 33]. VEGF, also known as vascular permeability factor (VPF), is a major angiogenic factor, with a specific affinity to endothelial cells (ECs). The function of VEGF activates blood vessel formation and homeostasis by stimulating migration, proliferation, and increased survival of endothelial cells in the hypoxic environment [7,34]. It is well accepted that the vascular network, in providing oxygen and nutrients, is essential for tissue development and repair, and thus VEGF may be a beneficial element for pulp regeneration [35]. BMPs belong to the transforming growth factor-\(\beta\) (TGF-\(\beta\)) superfamily of proteins, and are responsible for diverse biological functions. They act as potent regulators of proliferation, migration, and differentiation of MSCs into osteoblasts and chondroblasts, and thus they play a pivotal role in skeletal development [18,36]. In addition, in vivo and in vitro studies have shown the requirement of BMP activity in the early stages of odontogenesis [37], due to its ability to induce the transformation of pulp stem cells into odontoblasts [28]. Based on past findings, it has been suggested that BMPs may be a key element for dental tissue regeneration, especially recombinant human BMP-2, by virtue of its capability to convert adult pulp progenitor cells into odontoblast-like cells [38]. Studies conducted in animal models, including dogs, macaques, rats, and ferrets, revealed positive results for dentin formation when BMP-7 was placed in capping material over amputated dental pulp [28]. Interestingly, there are various recognized localizations of the reservoir of growth factors for endodontic therapies: the dentin matrix, platelet-rich fibrin, platelet-rich plasma, and blood clots [31,39,40].