Review Article | Open Access
Jun Kang, Wenguo Fan, Qianyi Deng, Hongwen He, Fang Huang, "Stem Cells from the Apical Papilla: A Promising Source for Stem Cell-Based Therapy", BioMed Research International, vol. 2019, Article ID 6104738, 8 pages, 2019. https://doi.org/10.1155/2019/6104738
Stem Cells from the Apical Papilla: A Promising Source for Stem Cell-Based Therapy
Stem cells are biological cells that can self-renew and can differentiate into multiple cell lineages. Stem cell-based therapy is emerging as a promising alternative therapeutic option for various disorders. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are isolated from various tissues and can be used as an alternative to embryonic stem cells. Stem cells from the apical papilla (SCAPs) are a novel population of MSCs residing in the apical papilla of immature permanent teeth. SCAPs present the characteristics of expression of MSCs markers, self-renewal, proliferation, migration, differentiation, and immunosuppression, which support the application of SCAPs in stem cell-based therapy, including the immunotherapy and the regeneration of dental tissues, bone, neural, and vascular tissues. In view of these properties and therapeutic potential, SCAPs can be considered as promising candidates for stem cell-based therapy. Thus the aim of our review was to summarize the current knowledge of SCAPs considering isolation, characterization, and multilineage differentiation. The prospects for their use in stem cell-based therapy were also discussed.
Stem cells are biological cells that can self-renew and can differentiate into multiple cell lineages. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are isolated from various tissues. Recently, dental-tissue-derived MSC-like populations have been isolated and characterized. Stem cells from the apical papilla (SCAPs) residing in the apical papilla of immature permanent teeth represent a novel population of dental MSCs that possesses the properties of high proliferative potential, the self-renewal ability, and low immunogenicity . Moreover, considerable evidence indicates that SCAPs are capable of giving rise to various lineages of cells, such as osteogenic, odontogenic, neurogenic, adipogenic, chondrogenic, and hepatogenic cells, which can be as a promising source for stem cell-based therapy (Figure 1) [1–4]. With the discovery of stem cells and the development of stem cell technology, stem cell-based therapy is emerging and moving rapidly into clinical application, which aims to replace or repair damaged cells and tissue in numerous diseases.
The aim of our review was to summarize the basics of biology of SCAPs, and the prospects for their use in stem cell-based therapy were also discussed.
2. Isolation of SCAPs
Recently, a variety of dental MSCs have been isolated, including dental pulp stem cells (DPSCs), stem cells from the human exfoliated deciduous teeth, SCAPs, dental follicle stem cells (DFSCs), and periodontal ligament stem cells (PDLSCs). In 2006, SCAPs were first discovered and isolated from the apical papilla tissue of incompletely developed tooth by Sonoyama et al. . The apical papilla refers to the soft tissue that is loosely attached to the apices of immature permanent teeth and can be easily detached with a pair of tweezers . There is a cell rich zone lying between the apical papilla and the pulp, and the apical papilla is different from the pulp in terms of containing less cellular and vascular components than the pulp . However, a previous study has provided evidence that the apical papilla contains a higher number of MSCs than mature dental pulp tissue . Currently, there are two common approaches to isolate and culture SCAPs. The first method is enzyme digestion. The apical papilla tissue is separated from the tip of the root, minced into pieces, and then digested in a solution of collagenase type I and dispase with gentle agitation. After digestion, tissue clumps are collected and passed through a cell strainer to obtain single cell suspension of SCAPs, which is then seeded in culture dishes . Another method is explant culture, in which the apical papilla tissue is cut into samples about 1 mm3 in size and then plated on culture dishes . Both methods can effectively isolate and culture SCAPs, but the former is more commonly used. Meanwhile, a noteworthy fact is that SCAPs can only be isolated at a certain stage of tooth development, because apical papilla evolves into dental pulp during the formation of crown and root. Since Ding et al. have confirmed that cryopreservation does not affect the biological and immunological properties of SCAPs ; SCAPs can be stored by cryopreservation to retain their regenerative potential for future clinical applications.
3. Characterizations of SCAPs
There is a large volume of published studies describing that SCAPs, like other MSCs, express the MSC-associated markers and are capable of self-renewal, proliferation, and multilineage differentiation . Comparative analyses indicate that SCAPs exhibit a higher proliferation rate than DPSCs and PDLSCs [1, 2, 7, 8] but display a lower proliferation rate than DFSCs . When stimulated with human platelet lysate, epiregulin, tumor necrosis factor α, or basic fibroblast growth factor (bFGF), SCAPs show a significantly increased proliferation rate [9–11]. In addition, compared with DPSCs, SCAPs have greater migration ability assessed by scratch assay . Several studies have investigated that a variety of chemotactic factors, including stromal cell-derived factor 1, transforming growth factor β 1, platelet-derived growth factor, granulocyte colony-stimulating factor, and FGF 2, could promote the migration of SCAPs. Therefore, these factors may be used clinically in cell homing-based regenerative endodontic procedures in the future [12–15].
SCAPs are also characterized by the expression of surface and intracellular molecules (Table 1). Similar to other MSCs, SCAPs express STRO-1 and CD146 that are recognized as early MSCs markers . They also express pluripotent markers such as octamer binding transcription factor-3/4, sex determining region Y-box 2, and nanog homeobox [3, 16]. In addition, several authors have reported the expression of a range of markers on SCAPs, including CD13, CD24, CD29, CD44, CD49, CD51, CD56, CD61, CD73, CD90, CD105, CD106, CD166, NOTCH3, and vimentin [1, 3, 16–20]. Meanwhile, SCAPs are found to be negative for the expression of CD14, CD18, CD34, CD45, CD117, and CD150, indicating that they are not of hematopoietic origin [1, 20]. Among these molecular markers, CD24 may be used to distinguish SCAPs from DPSCs and predict the differentiation of SCAPs, since it is undetectable in DPSCs . As for other markers, it seems to be expressed in both SCAPs and other MSCs, so specific markers need to be further developed. Moreover, SCAPs have a higher expression of antiapoptotic protein survivin, longer telomere length, and greater telomerase activity associated with cellular lifespan and cell proliferation than DPSCs do [1, 21].
Abbreviations: CD, Cluster of differentiation; Oct3/4, octamer binding transcription factor-3/4; Sox-2, sex determining region Y-box 2; Nanog, nanog homeobox.
Aside from these surface and intracellular molecules, the secretome of SCAPs has also been extensively profiled. The evidence indicates that a total of 2,046 proteins are released, including chemokines, angiogenic, immunomodulatory, antiapoptotic, neuroprotective factors, and extracellular matrix proteins. Significantly, SCAPs secrete more chemokines, neurotrophins and proteins involving in metabolic processes and transcription compared to bone marrow mesenchymal stem cells (BMMSCs) .
SCAPs are a heterogeneous population of cells, which contain subpopulations of cells with different phenotypes and characteristics . For example, the STRO-1 (pos)/CD146 (pos) subpopulation shows a higher proliferation rate and an enhanced odontogenic differentiation potential than other subpopulations . However, the causes of cellular heterogeneity are still unknown, so further studies are required.
4. Multilineage Differentiation
Over the past 10 years, numerous studies have confirmed that SCAPs possess the capacity to differentiate into multiple cell types such as osteoblasts, odontoblasts, neural cells, adipocytes, chondrocytes, and hepatocytes.
4.1. Osteo/Odontogenic Differentiation
Many studies have demonstrated that SCAPs are capable of differentiating into osteoblasts and odontoblasts [1, 2, 19, 20, 23]. After culture in osteo/odontogenic medium containing L-ascorbate-2-phosphate, dexamethasone, and β-glycerophosphate, SCAPs are found to express specific markers of osteoblasts or odontoblasts, such as alkaline phosphatase, runt-related transcription factor 2, osteocalcin, dentin sialophosphoprotein, bone sialoprotein, and dentin matrix protein 1 [3, 7, 16, 19, 20, 23–36]. They also form mineralized nodules which can be identified by alizarin red staining for calcium deposits [1–3, 23]. Furthermore, there are a large number of studies investigating the influence of molecules on the directed differentiation of SCAPs. The osteo/odontogenic differentiation of SCAPs can be promoted by forkhead c2 , bone morphogenetic protein 2 ( BMP2) [37–39], BMP9 [32, 40], SH3 and multiple ankyrin repeat domains 2 , GATA binding protein 4 , 17 β-estradiol , nuclear factor I-C [42, 43], secreted frizzled-related protein 2 (SFRP2) [44, 45], WD repeat domain 63 , insulin-like growth factor-1 [30, 46], recombinant human plasminogen activator inhibitor-1 , Rac1 gene , early growth response gene 1 , sirtuin 1 , potassium phosphate monobasic , canonical NF-kappaB signaling pathway , wnt/β -catenin signaling , and some dentin-derived proteins . By contrast, microRNA hsa-let-7b  and sonic hedgehog signaling  are able to inhibit this differentiation of SCAPs. In addition, homeobox (HOX) genes play important roles in the differentiation regulation of SCAPs. The results of investigations indicate that HOXB7 , distal-less homeobox 2 , and MEIS2  promote osteogenic differentiation of SCAPs, whereas HOXC10  inhibits this differentiation in vitro.
4.2. Neurogenic Differentiation
As neural crest-derived cells, SCAPs demonstrate neurogenic differentiation capacity in vitro after induction. Previous reports have provided evidence that, upon stimulation with a neurogenic medium containing B27 supplement, bFGF, and epidermal growth factor (EGF), SCAPs express a variety of markers of neural precursors, neuron, and glial cells, such as nestin, neurogenin 2, musashi 1, neuronal nuclei, neuron-specific enolase, βIII tubulin, microtubule associated protein 2, neurofilament, glial fibrillary acidic protein, 2′, 3′-cyclic nucleotide-3′ phosphodiesterase, glutamic acid decarboxylase, and neural cell adhesion molecule [2, 16, 20, 56–60]. Moreover, several studies investigate that fibrinogen 50-thrombin 50 and SFRP2 could promote neurogenic differentiation of SCAPs [61, 62].
4.3. Other Lineage Differentiations
The plasticity of SCAPs enables them to differentiate into other cell lineages. For example, after induction with adipogenic medium, SCAPs can form characteristic oil red O-positive lipid-containing adipocytes [1–4, 20, 60]. This phenotypic conversion is also correlated with the expression of adipocyte-specific markers, such as adipocyte fatty acid binding protein 2, peroxisome proliferator-activated receptor-γ2 and lipoprotein lipase [3, 4]. The ability of SCAPs to differentiate into chondrocytes in vitro has also been noted. Under appropriate culture conditions, SCAPs can express chondrogenic differentiation markers such as SRY-box 9 and collagen type II and form cartilage as identified by alcian blue staining [3, 4, 20, 60]. In addition, SCAPs can be induced in vitro to differentiate into hepatocytes, characterized by the production of urea and the expression of hepatic-specific markers, such as hepatocyte nuclear factor 1-α, α-1 fetoprotein, alanine amino transferase, and aspartate amino transferase [3, 63].
These results provide insight into the differentiation of SCAPs. However, the mechanisms underlying the directed differentiation remain unclear, which need to be further investigated.
5. Therapeutic Potential of SCAPs
Stem cell-based therapy is an emerging field as a promising medical treatment of multiple diseases . SCAPs have the ability to differentiate into various cell types and possess low immunogenicity, which could contribute to the regeneration and repair of tissues. Hence they can be considered as an attractive alternative cell source for stem cell-based therapy.
5.1. Pulp-Dentin Regeneration
Irreversible pulpitis and periapical periodontitis, usually caused by dental trauma and caries, are common diseases in oral cavity. In recent years, regenerative endodontics has been a promising treatment for these diseases instead of apexification. SCAPs are characterized by a high proliferation rate and odontogenic differentiation potential, which makes them suitable for stem cell-based regeneration and producing dentin-pulp complex. After transplantation of SCAPs combined with hydroxyapatite/tricalcium phosphate (HA/TCP) scaffolds into immunocompromised mice, a layer of dentin tissue is generated on the surface of the HA/TCP . When SCAPs are seeded onto synthetic scaffolds consisting of poly-D, L-lactide/glycolide, inserted into tooth fragments and transplanted into immunocompromised mice, a continuous layer of dentin-like tissue is deposited on the dentin surface and vascularized pulp-like tissue is formed in the root canal . Many researchers have invented novel scaffolds for regenerative endodontics, including decellularized dental pulp [66, 67] and injectable nanofibrous microspheres . Functionalized scaffolds can be used as a controlled-release device for morphogenic factors to provide a conductive microenvironment for odontogenic differentiation of stem cells and pulp-dentin regeneration . In addition, scaffold-free stem cell sheet-derived pellet (CSDP) can be used in pulp-dentin regeneration. The evidence indicates that SCAPs-based CSDPs transplanted into immunocompromised mice also yield pulp-dentin-like tissue . Although previous studies have demonstrated the potential of SCAPs in pulp-dentin regeneration, more researches are needed in order to achieve clinical application.
5.2. Bioroot Engineering
Tooth loss caused by a variety of diseases such as trauma, caries, periodontal disease, and genetic disorders can lower the quality of life. Currently, dental implants are regarded as the best clinical method for replacing missing tooth instead of fixed bridge and removable denture. However, with the development of tissue engineering and regenerative medicine, tooth regeneration has become an ideal and promising method. Some case reports show continued root development after conservative treatment of immature permanent teeth with pulp necrosis and periapical lesions. This clinical phenomenon suggests that SCAPs may survive during the process of pulp necrosis and play an important role in tooth root formation by differentiating into odontoblasts [2, 70, 71]. Sonoyama et al. have demonstrated that by using SCAPs along with the PDLSCs to regenerate a bioroot with periodontal ligament tissues. A minipig model is used, and the autologous SCAPs and PDLSCs are then seeded into a root-shaped scaffold with a postchannel in the middle, and implanted into a socket of alveolar bone. Three months later, the bioroot is formed and can support a porcelain crown to provide normal tooth function. Compared with dental implants, the bioroot is encircled with periodontal ligament tissue and has favorable biomechanical properties . However, there has only been limited study of tooth root regeneration, so more researches are required to reach the potential of SCAPs in bioroot engineering.
5.3. Periodontal Tissue Regeneration
Periodontitis, one of the most widespread chronic infectious diseases, results in the destruction of tooth-supporting tissues and associates with many systemic diseases. Conventional treatments for periodontitis, including scaling, root planning, and periodontal flap surgery, can only alleviate the inflammation of periodontal tissues and form a long junctional epithelium instead of periodontal attachment, so alternative regeneration methods are necessary to regenerate periodontal tissues. Recently, stem cell-based therapy is considered highly promising for periodontal tissue regeneration. 12 weeks after injecting SCAPs into periodontitis animal model, clinical assessments, CT scans, and histopathology results show that SCAPs could significantly improve periodontal regeneration . This study supports the concept of using SCAPs as a suitable alternative stem cell source for periodontal tissue regeneration in the future.
5.4. Bone Regeneration
Recently, with the development of biocompatible materials and the discovery of stem cell sources, bone tissue engineering has become an alternative approach for repairing large bone defects instead of bone grafting. As mentioned earlier, ex vivo expanded SCAPs have the capacity to differentiate into osteoblasts after culture in osteogenic medium. To further investigate the potential to form bone tissue, SCAPs combined with scaffolds are implanted subcutaneously into immunocompromised mice. After a period of time, ectopic bone-like tissue is generated, which contains osteocyte-like cells and osteoblast-like cells [1, 5, 19]. These results indicate the feasibility of SCAPs transplantation in the treatment of bone defects, but extensive work lies ahead in order to achieve clinical application.
5.5. Neural Regeneration and Repair
SCAPs derived from the cranial neural crest have the capacity to differentiate into neural cells under inductive conditions. Therefore they may be a potential cell source for the treatment of nerve injuries. To regenerate nerve tissue, researchers have attempted to cultivate SCAPs in 3D organotypic culture, which eventually generate 3D cell-based nerve-like tissue with axons and myelin structures in vitro . Moreover, in a rat hemisection model of spinal cord injury, transplantation of apical papilla tissue into the lesion site can improve gait and reduce glial reactivity . Another study indicates that transplanted SCAPs can protect spinal cord neurons and promote functional recovery after spinal cord injury . Additionally, in a rat sciatic nerve injury model, SCAPs also exert neuroprotective effects on the dorsal root ganglia neurons and stimulate axon regeneration . Previous reports suggest that SCAPs are able to secrete neurotrophic factors such as nerve growth factor, brain derived neurotropic factor, neurotrophin-3, and activin-A [76–78]. Taken together, these observations seem to indicate that SCAPs are excellent candidates for stem cell-based therapy in central and peripheral nerve injuries.
Ischemic disease is a major cause of disability and death. Currently, stem cell-based therapeutic angiogenesis is an alternative treatment for ischemic diseases. In recent years, the transdifferentiation capacity of SCAPs into endothelial cells has been evaluated. After exposure to angiogenic medium, SCAPs can undergo morphological changes to endothelial cells, express higher levels of several angiogenesis-related genes, and form capillary-like structures in vitro . Furthermore, a series of experiments have shown that SCAPs possess the ability to promote angiogenesis. SCAPs can secrete several proangiogenic molecules that are able to improve the angiogenic potential of endothelial cells, such as angiogenin, VEGF, and insulin-like growth factor binding protein 3 [79, 80]. A chorioallantoic membrane assay demonstrates that SCAPs also stimulate new blood vessel formation in an in vivo setting . Especially under hypoxic conditions, the proangiogenic effect of SCAPs is increased [81, 82]. These results indicate that, due to their angiogenic potential, SCAPs are attractive options for stem cell-based therapeutic angiogenesis.
In addition to multilineage differentiation capacity, SCAPs possess immunomodulatory functions, which indicate that they may be a potential immunotherapeutic tool for treating autoimmune and inflammation-related diseases. Previous research confirms that SCAPs express low levels of immunological molecules, such as swine leukocyte antigen (SLA) class I molecules and SLA class II DR molecules in a minipig model. Moreover, SCAPs are capable of inhibiting T cell proliferation in vitro through an apoptosis-independent mechanism . From these studies, it is apparent that SCAPs have immunosuppressive properties, but the exact mechanisms remain unknown. So there are still challenges to be solved before SCAPs can be applied clinically.
In conclusion, the isolation of SCAPs from dental tissue along with discovery of their properties has provided a conceptual framework of their nature and potential application. However, several aspects of SCAPs biology remain in question and unsettled, which include the identity, nature, standardization of isolation and culture protocols, cell banking procedures, and in vivo use for therapy. More progress on stem cells made in nondental tissues will help in adopting research strategies used in SCAPs. Simultaneously, a better understanding of the novel population of postnatal somatic stem cells could facilitate the full utilization of stem cells in clinical practice.
Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this paper.
This work was supported partly by the National Natural Science Foundation of China [Grants nos. 81870737, 81771098, and 81470760] and Undergraduate Entrepreneurship Training and Entrepreneurship Practice Project of Sun Yat-sen University [Grant no. 201801424].
- W. Sonoyama, Y. Liu, D. Fang et al., “Mesenchymal stem cell-mediated functional tooth regeneration in Swine,” PLoS ONE, vol. 1, no. 1, article no e79, 2006.
- W. Sonoyama, Y. Liu, T. Yamaza et al., “Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: a pilot study,” Journal of Endodontics, vol. 34, no. 2, pp. 166–171, 2008.
- R. Patil, B. M. Kumar, W.-J. Lee et al., “Multilineage potential and proteomic profiling of human dental stem cells derived from a single donor,” Experimental Cell Research, vol. 320, no. 1, pp. 92–107, 2014.
- R. Dong, R. Yao, J. Du, S. Wang, and Z. Fan, “Depletion of histone demethylase KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of stem cells from apical papilla,” Experimental Cell Research, vol. 319, no. 18, pp. 2874–2882, 2013.
- S. Abe, S. Yamaguchi, A. Watanabe, K. Hamada, and T. Amagasa, “Hard tissue regeneration capacity of apical pulp derived cells (APDCs) from human tooth with immature apex,” Biochemical and Biophysical Research Communications, vol. 371, no. 1, pp. 90–93, 2008.
- G. Ding, W. Wang, Y. Liu et al., “Effect of cryopreservation on biological and immunological properties of stem cells from apical papilla,” Journal of Cellular Physiology, vol. 223, no. 2, pp. 415–422, 2010.
- G. Lei, M. Yan, Z. Wang et al., “Dentinogenic capacity: Immature root papilla stem cells versus mature root pulp stem cells,” Biology of the Cell, vol. 103, no. 4, pp. 185–196, 2011.
- K. Chen, H. Xiong, Y. Huang, and C. Liu, “Comparative analysis of in vitro periodontal characteristics of stem cells from apical papilla (SCAP) and periodontal ligament stem cells (PDLSCs),” Archives of Oral Biolog, vol. 58, no. 8, pp. 997–1006, 2013.
- D. Abuarqoub, A. Awidi, and N. Abuharfeil, “Comparison of osteo/odontogenic differentiation of human adult dental pulp stem cells and stem cells from apical papilla in the presence of platelet lysate,” Archives of Oral Biolog, vol. 60, no. 10, pp. 1545–1553, 2015.
- Y. Cao, D. S. Xia, S. R. Qi et al., “Epiregulin can promote proliferation of stem cells from the dental apical papilla via MEK/Erk and JNK signalling pathways,” Cell Proliferation, vol. 46, no. 4, pp. 447–456, 2013.
- J. Wu, G. T.-J. Huang, W. He et al., “Basic fibroblast growth factor enhances stemness of human stem cells from the apical papilla,” Journal of Endodontics, vol. 38, no. 5, pp. 614–622, 2012.
- S. Fayazi, K. Takimoto, and A. Diogenes, “Comparative Evaluation of Chemotactic Factor Effect on Migration and Differentiation of Stem Cells of the Apical Papilla,” Journal of Endodontics, vol. 43, no. 8, pp. 1288–1293, 2017.
- X. Chen, J. Liu, L. Yue, G. T. Huang, and X. Zou, “Phosphatidylinositol 3-Kinase and Protein Kinase C Signaling Pathways Are Involved in Stromal Cell–derived Factor-1α–mediated Transmigration of Stem Cells from Apical Papilla,” Journal of Endodontics, vol. 42, no. 7, pp. 1076–1081, 2016.
- S. Kwon, S. Kim, J. Yoon, and S. Ahn, “Transforming growth factor beta1-induced heat shock protein 27 activation promotes migration of mouse dental papilla-derived MDPC-23 cells,” Journal of Endodontics, vol. 36, no. 8, pp. 1332–1335, 2010.
- J.-Y. Liu, X. Chen, L. Yue, G. T.-J. Huang, and X.-Y. Zou, “CXC Chemokine Receptor 4 Is Expressed Paravascularly in Apical Papilla and Coordinates with Stromal Cell-derived Factor-1α during Transmigration of Stem Cells from Apical Papilla,” Journal of Endodontics, vol. 41, no. 9, pp. 1430–1436, 2015.
- A. Bakopoulou, G. Leyhausen, J. Volk, P. Koidis, and W. Geurtsen, “Comparative characterization of STRO-1(neg)/CD146(pos) and STRO-1(pos)/CD146(pos) apical papilla stem cells enriched with flow cytometry,” Archives of Oral Biolog, vol. 58, no. 10, pp. 1556–1568, 2013.
- N. B. Ruparel, J. F. A. De Almeida, M. A. Henry, and A. Diogenes, “Characterization of a stem cell of apical papilla cell line: Effect of passage on cellular phenotype,” Journal of Endodontics, vol. 39, no. 3, pp. 357–363, 2013.
- M. Jamal, S. M. Chogle, S. M. Karam, and G. T.-J. Huang, “NOTCH3 is expressed in human apical papilla and in subpopulations of stem cells isolated from the tissue,” Genes and Diseases, vol. 2, no. 3, pp. 261–267, 2015.
- E. Ikeda, M. Hirose, N. Kotobuki et al., “Osteogenic differentiation of human dental papilla mesenchymal cells,” Biochemical and Biophysical Research Communications, vol. 342, no. 4, pp. 1257–1262, 2006.
- S. Abe, S. Yamaguchi, and T. Amagasa, “Multilineage Cells from Apical Pulp of Human Tooth with Immature Apex,” Oral Science International, vol. 4, no. 1, pp. 45–58, 2007.
- B.-G. Jeon, E.-J. Kang, B. Mohana Kumar et al., “Comparative analysis of telomere length, telomerase and reverse transcriptase activity in human dental stem cells,” Cell Transplantation, vol. 20, no. 11-12, pp. 1693–1705, 2011.
- S. Yu, Y. Zhao, Y. Ma, and L. Ge, “Profiling the secretome of human stem cells from dental apical papilla,” Stem Cells and Development, vol. 25, no. 6, pp. 499–508, 2016.
- S. Tetè, E. Nargi, F. Mastrangelo et al., “Changes in matrix extracellular phosphoglycoprotein expression before and during in vitro osteogenic differentiation of human dental papilla mesenchymal cells,” International Journal of Immunopathology and Pharmacology, vol. 21, no. 2, pp. 309–318, 2008.
- Q. Gao, J. Ge, Y. Ju et al., “Roles of L-type calcium channels (CaV1.2) and the distal C-terminus (DCT) in differentiation and mineralization of rat dental apical papilla stem cells (rSCAPs),” Archives of Oral Biolog, vol. 74, pp. 75–81, 2017.
- L. Guo, L. Jin, and J. Du, “Depletion of SHANK2 inhibited the osteo/dentinogenic differentiation potentials of stem cells from apical papilla,” Histology and Histopathology, vol. 32, no. 5, pp. 471–479, 2017.
- B. Jin and P. Choung, “Recombinant human plasminogen activator inhibitor-1 accelerates odontoblastic differentiation of human stem cells from apical papilla,” Tissue Engineering Part A, vol. 22, no. 9-10, pp. 721–732, 2016.
- J. Li, M. Yan, Z. Wang et al., “Effects of Canonical NF-κB Signaling Pathway on the Proliferation and Odonto/Osteogenic Differentiation of Human Stem Cells from Apical Papilla,” BioMed Research International, vol. 2014, Article ID 319651, 12 pages, 2014.
- Y. Li, M. Yan, Z. Wang et al., “17beta-estradiol promotes the odonto/osteogenic differentiation of stem cells from apical papilla via mitogen-activated protein kinase pathway,” Stem Cell Research & Therapy, vol. 5, no. 6, p. 125, 2014.
- C. Liu, H. Xiong, K. Chen, Y. Huang, and X. Yin, “Long-term exposure to pro-inflammatory cytokines inhibits the osteogenic/dentinogenic differentiation of stem cells from the apical papilla,” International Endodontic Journal, vol. 49, no. 10, pp. 950–959, 2016.
- S. Ma, G. Liu, L. Jin et al., “IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla,” Scientific Reports, vol. 6, no. 1, article no 36922, 2016.
- J. Ren, G. Liang, L. Gong, B. Guo, and H. Jiang, “Rac1 Regulates the Proliferation, Adhesion, Migration, and Differentiation of MDPC-23 Cells,” Journal of Endodontics, vol. 43, no. 4, pp. 580–587, 2017.
- J. Wang, H. Zhang, W. Zhang et al., “Bone morphogenetic protein-9 effectively induces osteo/odontoblastic differentiation of the reversibly immortalized stem cells of dental apical papilla,” Stem Cells and Development, vol. 23, no. 12, pp. 1405–1416, 2014.
- B. W. Park, Y. S. Hah, M. J. Choi et al., “In vitro osteogenic differentiation of cultured human dental papilla-derived cells,” Journal of Oral & Maxillofacial Surgery, vol. 67, no. 3, pp. 507–514, 2009.
- S. Diao, D.-M. Yang, R. Dong et al., “Enriched trimethylation of lysine 4 of histone H3 of WDR63 enhanced osteogenic differentiation potentials of stem cells from apical papilla,” Journal of Endodontics, vol. 41, no. 2, pp. 205–211, 2015.
- R. T. Gao, L. P. Zhan, C. Meng, and etal., “Homeobox B7 promotes the osteogenic differentiation potential of mesenchymal stem cells by activating RUNX2 and transcript of BSP,” International Journal of Clinical and Experimental Medicine, vol. 8, no. 7, pp. 10459–10470, 2015.
- G. Li, N. Han, H. Yang et al., “Homeobox C10 inhibits the osteogenic differentiation potential of mesenchymal stem cells,” Connective Tissue Research, pp. 1–11, 2017.
- W. Zhang, X. Zhang, J. Li et al., “Foxc2 and BMP2 Induce Osteogenic/Odontogenic Differentiation and Mineralization of Human Stem Cells from Apical Papilla,” Stem Cells International, vol. 2018, pp. 1–10, 2018.
- W. Zhang, X. Zhang, J. Ling et al., “Proliferation and odontogenic differentiation of BMP2 gene-transfected stem cells from human tooth apical papilla: An In Vitro Study,” International Journal of Molecular Medicine, vol. 34, no. 4, pp. 1004–1012, 2014.
- W. Zhang, X. Zhang, J. Ling, X. Wei, and Y. Jian, “Osteo-/odontogenic differentiation of BMP2 and VEGF gene-co-transfected human stem cells from apical papilla,” Molecular Medicine Reports, vol. 13, no. 5, pp. 3747–3754, 2016.
- H. Zhang, J. Wang, F. Deng et al., “Canonical Wnt signaling acts synergistically on BMP9-induced osteo/odontoblastic differentiation of stem cells of dental apical papilla (SCAPs),” Biomaterials, vol. 39, pp. 145–154, 2015.
- S. Guo, Y. Zhang, T. Zhou et al., “Role of GATA binding protein 4 (GATA4) in the regulation of tooth development via GNAI3,” Scientific Reports, vol. 7, no. 1, article no 1534, 2017.
- S. Gao, Y.-M. Zhao, and L.-H. Ge, “Nuclear factor I-C expression pattern in developing teeth and its important role in odontogenic differentiation of human molar stem cells from the apical papilla,” European Journal of Oral Sciences, vol. 122, no. 6, pp. 382–390, 2014.
- J. Zhang, Z. Wang, Y. Jiang et al., “Nuclear Factor I-C promotes proliferation and differentiation of apical papilla-derived human stem cells in vitro,” Experimental Cell Research, vol. 332, no. 2, pp. 259–266, 2015.
- L. Jin, Y. Cao, G. Yu et al., “SFRP2 enhances the osteogenic differentiation of apical papilla stem cells by antagonizing the canonical WNT pathway,” Cellular & Molecular Biology Letters, vol. 22, no. 1, article no 14, 2017.
- G. Yu, J. Wang, X. Lin et al., “Demethylation of SFRP2 by histone demethylase KDM2A regulated osteo-/dentinogenic differentiation of stem cells of the apical papilla,” Cell Proliferation, vol. 49, no. 3, pp. 330–340, 2016.
- S. Wang, J. Mu, Z. Fan et al., “Insulin-like growth factor 1 can promote the osteogenic differentiation and osteogenesis of stem cells from apical papilla,” Stem Cell Research, vol. 8, no. 3, pp. 346–356, 2012.
- T. Press, S. Viale-Bouroncle, O. Felthaus, M. Gosau, and C. Morsczeck, “EGR1 supports the osteogenic differentiation of dental stem cells,” International Endodontic Journal, vol. 48, no. 2, pp. 185–192, 2015.
- Q.-B. Zhang, W. Cao, Y.-R. Liu, S.-M. Cui, and Y.-Y. Yan, “Effects of Sirtuin 1 on the proliferation and osteoblastic differentiation of periodontal ligament stem cells and stem cells from apical papilla,” Genetics and Molecular Research, vol. 15, no. 1, 2016.
- L. Wang, M. Yan, Y. Wang et al., “Proliferation and osteo/odontoblastic differentiation of stem cells from dental apical papilla in mineralization-inducing medium containing additional KH2PO4,” Cell Proliferation, vol. 46, no. 2, pp. 214–222, 2013.
- J. Wang, B. Liu, S. Gu, and J. Liang, “Effects of Wnt/β-catenin signalling on proliferation and differentiation of apical papilla stem cells,” Cell Proliferation, vol. 45, no. 2, pp. 121–131, 2012.
- E. Piva, A. F. Silva, and J. E. Nör, “Functionalized scaffolds to control dental pulp stem cell fate,” Journal of Endodontics, vol. 40, no. 4, pp. S33–S40, 2014.
- Y. Wang, X. Pang, J. Wu et al., “MicroRNA hsa-let-7b suppresses the odonto/osteogenic differentiation capacity of stem cells from apical papilla by targeting MMP1,” Journal of Cellular Biochemistry, vol. 119, no. 8, pp. 6545–6554, 2018.
- Q. Jiang, X. Yin, Z. Shan et al., “Shh signaling, negatively regulated by BMP signaling, inhibits the osteo/dentinogenic differentiation potentials of mesenchymal stem cells from apical papilla,” Molecular and Cellular Biochemistry, vol. 383, no. 1-2, pp. 85–93, 2013.
- B. Qu, O. Liu, X. Fang et al., “Distal-less homeobox 2 promotes the osteogenic differentiation potential of stem cells from apical papilla,” Cell and Tissue Research, vol. 357, pp. 133–143, 2014.
- Z. Wu, J. Wang, R. Dong, and etal., “Depletion of MEIS2 inhibits osteogenic differentiation potential of human dental stem cells,” International Journal of Clinical and Experimental Medicine, vol. 8, no. 5, pp. 7220–7230, 2015.
- B.-C. Kim, S.-M. Jun, S. Y. Kim et al., “Engineering three dimensional micro nerve tissue using postnatal stem cells from human dental apical papilla,” Biotechnology and Bioengineering, vol. 114, no. 4, pp. 903–914, 2017.
- J. Lee, S. Um, I. Song, H. Y. Kim, and B. M. Seo, “Neurogenic differentiation of human dental stem cells,” Journal of the Korean Association of Oral and Maxillofacial Surgeons, vol. 40, no. 4, pp. 173–180, 2014.
- C. Yang, L. Sun, X. Li et al., “The potential of dental stem cells differentiating into neurogenic cell lineage after cultivation in different modes in vitro,” Cellular Reprogramming, vol. 16, no. 5, pp. 379–391, 2014.
- I. El Ayachi, J. Zhang, X.-Y. Zou et al., “Human dental stem cell derived transgene-free iPSCs generate functional neurons via embryoid body-mediated and direct induction methods,” Journal of Tissue Engineering and Regenerative Medicine, vol. 12, no. 4, pp. e1836–e1851, 2017.
- S. Abe, K. Hamada, M. Miura, and S. Yamaguchi, “Neural crest stem cell property of apical pulp cells derived from human developing tooth,” Cell Biology International, vol. 36, no. 10, pp. 927–936, 2012.
- X. Lin, R. Dong, S. Diao et al., “SFRP2 enhanced the adipogenic and neuronal differentiation potentials of stem cells from apical papilla,” Cell Biology International, vol. 41, no. 5, pp. 534–543, 2017.
- L. Germain, P. De Berdt, J. Vanacker et al., “Fibrin hydrogels to deliver dental stem cells of the apical papilla for regenerative medicine,” Journal of Regenerative Medicine, vol. 10, no. 2, pp. 153–167, 2015.
- A. Kumar, V. Kumar, V. Rattan, V. Jha, A. Pal, and S. Bhattacharyya, “Molecular spectrum of secretome regulates the relative hepatogenic potential of mesenchymal stem cells from bone marrow and dental tissue,” Scientific Reports, vol. 7, no. 1, article no 15015, 2017.
- R. E. Fitzsimmons, M. S. Mazurek, A. Soos, and C. A. Simmons, “Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering,” Stem Cells International, vol. 2018, pp. 1–16, 2018.
- G. T.-J. Huang, T. Yamaza, L. D. Shea et al., “Stem/progenitor cell-mediated de novo regeneration of dental pulp with newly deposited continuous layer of dentin in an in vivo model,” Tissue Engineering Part A, vol. 16, no. 2, pp. 605–615, 2010.
- J. Song, K. Takimoto, M. Jeon, J. Vadakekalam, N. Ruparel, and A. Diogenes, “Decellularized Human Dental Pulp as a Scaffold for Regenerative Endodontics,” Journal of Dental Research, vol. 96, no. 6, pp. 640–646, 2017.
- L. Hu, Z. Gao, J. Xu et al., “Decellularized swine dental pulp as a bioscaffold for pulp regeneration,” BioMed Research International, vol. 2017, Article ID 9342714, 9 pages, 2017.
- W. Wang, M. Dang, Z. Zhang et al., “Dentin regeneration by stem cells of apical papilla on injectable nanofibrous microspheres and stimulated by controlled BMP-2 release,” Acta Biomaterialia, vol. 36, pp. 63–72, 2016.
- S. Na, H. Zhang, F. Huang et al., “Regeneration of dental pulp/dentine complex with a three-dimensional and scaffold-free stem-cell sheet-derived pellet,” Journal of Tissue Engineering and Regenerative Medicine, vol. 10, no. 3, pp. 261–270, 2016.
- L.-H. Chueh and G. T.-J. Huang, “Immature Teeth With Periradicular Periodontitis or Abscess Undergoing Apexogenesis: A Paradigm Shift,” Journal of Endodontics, vol. 32, no. 12, pp. 1205–1213, 2006.
- G. T.-J. Huang, W. Sonoyama, Y. Liu, H. Liu, S. Wang, and S. Shi, “The hidden treasure in apical papilla: the potential role in pulp/dentin regeneration and bioroot engineering,” Journal of Endodontics, vol. 34, no. 6, pp. 645–651, 2008.
- G. Li, N. Han, X. Zhang et al., “Local Injection of Allogeneic Stem Cells from Apical Papilla Enhanced Periodontal Tissue Regeneration in Minipig Model of Periodontitis,” BioMed Research International, vol. 2018, Article ID 3960798, 8 pages, 2018.
- P. De Berdt, J. Vanacker, B. Ucakar et al., “Dental apical papilla as therapy for spinal cord injury,” Journal of Dental Research, vol. 94, no. 11, pp. 1575–1581, 2015.
- C. Yang, X. Li, L. Sun, W. Guo, and W. Tian, “Potential of human dental stem cells in repairing the complete transection of rat spinal cord,” Journal of Neural Engineering, vol. 14, no. 2, Article ID 026005, 2017.
- M. K. Kolar, V. N. Itte, P. J. Kingham, L. N. Novikov, M. Wiberg, and P. Kelk, “The neurotrophic effects of different human dental mesenchymal stem cells,” Scientific Reports, vol. 7, no. 1, Article ID 12605, 2017.
- A. Kumar, V. Kumar, V. Rattan, V. Jha, and S. Bhattacharyya, “Secretome Cues Modulate the Neurogenic Potential of Bone Marrow and Dental Stem Cells,” Molecular Neurobiology, vol. 54, no. 6, pp. 4672–4682, 2017.
- P. De Berdt, P. Bottemanne, J. Bianco et al., “Stem cells from human apical papilla decrease neuro-inflammation and stimulate oligodendrocyte progenitor differentiation via activin-A secretion,” Cellular and Molecular Life Sciences, vol. 75, no. 15, pp. 2843–2856, 2018.
- J. F. De Almeida, P. Chen, M. A. Henry, and A. Diogenes, “Stem cells of the apical papilla regulate trigeminal neurite outgrowth and targeting through a BDNF-dependent mechanism,” Tissue Engineering Part A, vol. 20, no. 23-24, pp. 3089–3100, 2014.
- A. Bakopoulou, A. Kritis, D. Andreadis et al., “Angiogenic potential and secretome of human apical papilla mesenchymal stem cells in various stress microenvironments,” Stem Cells and Development, vol. 24, no. 21, pp. 2496–2512, 2015.
- P. Hilkens, Y. Fanton, W. Martens et al., “Pro-angiogenic impact of dental stem cells in vitro and in vivo,” Stem Cell Research, vol. 12, no. 3, pp. 778–790, 2014.
- C. Yuan, P. Wang, L. Zhu et al., “Coculture of stem cells from apical papilla and human umbilical vein endothelial cell under hypoxia increases the formation of three-dimensional vessel-like structures in vitro,” Tissue Engineering Part A, vol. 21, no. 5-6, pp. 1163–1172, 2015.
- J. Vanacker, A. Viswanath, P. De Berdt et al., “Hypoxia modulates the differentiation potential of stem cells of the apical papilla,” Journal of Endodontics, vol. 40, no. 9, pp. 1410–1418, 2014.
- G. Ding, Y. Liu, Y. An et al., “Suppression of T cell proliferation by root apical papilla stem cells in vitro,” Cells Tissues Organs, vol. 191, no. 5, pp. 357–364, 2010.
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