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Stem Cell Reviews and Reports

, Volume 15, Issue 1, pp 67–81 | Cite as

Human Dental Pulp Stem Cells and Gingival Mesenchymal Stem Cells Display Action Potential Capacity In Vitro after Neuronogenic Differentiation

  • Dong Li
  • Xiao-Ying Zou
  • Ikbale El-Ayachi
  • Luis O. Romero
  • Zongdong Yu
  • Alejandro Iglesias-Linares
  • Julio F. Cordero-Morales
  • George T.-J. HuangEmail author
Article
First Online:

Abstract

The potential of human mesenchymal stromal/stem cells (MSCs) including oral stem cells (OSCs) as a cell source to derive functional neurons has been inconclusive. Here we tested a number of human OSCs for their neurogenic potential compared to non-OSCs and employed various neurogenic induction methods. OSCs including dental pulp stem cells (DPSCs), gingiva-derived mesenchymal stem cells (GMSCs), stem cells from apical papilla and non-OSCs including bone marrow MSCs (BMMSCs), foreskin fibroblasts and dermal fibroblasts using non-neurosphere-mediated or neurosphere-mediated methods to guide them toward neuronal lineages. Cells were subjected to RT-qPCR, immunocytofluorescence to detect the expression of neurogenic genes or electrophysiological analysis at final stage of maturation. We found that induced DPSCs and GMSCs overall appeared to be more neurogenic compared to other cells either morphologically or levels of neurogenic gene expression. Nonetheless, of all the neural induction methods employed, only one neurosphere-mediated method yielded electrophysiological properties of functional neurons. Under this method, cells expressed increased neural stem cell markers, nestin and SOX1, in the first phase of differentiation. Neuronal-like cells expressed βIII-tubulin, CNPase, GFAP, MAP-2, NFM, pan-Nav, GAD67, Nav1.6, NF1, NSE, PSD95, and synapsin after the second phase of differentiation to maturity. Electrophysiological experiments revealed that 8.3% of DPSC-derived neuronal cells and 21.2% of GMSC-derived neuronal cells displayed action potential, although no spontaneous excitatory/inhibitory postsynaptic action potential was observed. We conclude that DPSCs and GMSCs have the potential to become neuronal cells in vitro, therefore, these cells may be used as a source for neural regeneration.

Keywords

Oral stem cells OSCs Adult stem cells Neural stem cells NSCs Neurogenesis Neurosphere Neurons Dental pulp stem cells Gingival mesenchymal stem cells Immunocytofluorescence qPCR Electrophysiology Patch clamp Action potential 

Abbreviations

AP

Action potential

BM

Bone marrow

BSA

Bovine serum albumin

DAPI

4′,6-diamidino-2-phenylindole dihydrochloride

DFs

Human dermal fibroblasts

DPSCs

Dental pulp stem cells

FFs

Human foreskin fibroblasts

GMSCs

Gingiva-derived mesenchymal stem cells

hESC

Human embryonic stem cell

iPSCs

Induced pluripotent stem cells

MSCs

Mesenchymal Stromal/Stem Cells

NDM

Neural differentiation medium

NMM

Neurogenic maturation medium

NSC

Neural stem/progenitor cell

OSCs

Oral stem cells

PD

Population doubling

qPCR

Quantitative real-time polymerase chain reaction

SCAP

Stem cell of apical papilla

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Notes

Acknowledgments

The authors thank Dr. Kristen O’Connell (UTHSC) for her assistance during the early developmental stage of the project; Dr. Rebeca Caires Mugarra (UTHSC) for initial assistance in the patch-clamp studies; and UTHSC Biostatistic BERD Consulting Program for statistical support.

Authors’ Contributions

DL designed and performed the experimental work, acquired, assembled, analyzed the data, and drafted/revised the manuscript. XYZ initiated the project and along with IEA, LOR, ZY, and AIL performed some of the experimental work, assembled, analyzed the data and drafted/revised part of the manuscript. JFCM supervised some of the experimental work, assembled, analyzed the data and drafted/revised part of the manuscript. GTJH conceived, designed, performed experimental works and supervised the overall project, analyzed and interpreted the data and finalized the manuscript. All authors have read and approved the manuscript for publication.

Funding

This work was supported in part by grants from the National Institutes of Health R01 DE019156 (G.T.-J.H.), AHA 15SDG25700146 (J.F.C.), National Institutes of Health R01 GM125629–01 (J.F.C-M) and a Research Fund from the University of Tennessee Health Science Center (G.T.-J.H.).

Compliance with Ethical Standards

Ethics Approval and Consent to Participate

To be discarded extracted teeth were collected from Clinics at Boston University (BU) and University of Tennessee Health Science Center (UTHSC) based on exempt protocols approved by the respective Medical Institutional Review Board (BU: #H-28882; and UTHSC:#12–01937-XM).

Consent for Publication

This manuscript has been approved by all authors and is solely the work of the authors named.

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

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Supplemental Table S1 (DOC 54 kb)
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Supplemental Table S2 (DOCX 21 kb)
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Supplemental Table S3 (DOCX 16 kb)
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Supplemental Table S4 (DOCX 15 kb)
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Supplemental Table S5 (DOCX 27 kb)
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Supplemental Fig. 1

RT-PCR analysis of the expression of neural markers at day 0 (before induction). Donor information is the same as that in Fig. 2. (PNG 189 kb)

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High resolution image (TIF 3382 kb)
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Supplemental Fig. 2

qPCR analysis of non-neurosphere mediated neurogenic induction (NDM-C). Representative data measured in triplicate showing various neurogenic gene expression in OSCs and BMMSCs at 0, 7, 21 and 35 days following induction. OSCs: DPSCs (donor: 18-yr female, passage 3); SCAP (donor: 17 yr. female, p3); GMSCs. (donor: 53 yr. male, p4). BMMSCs (20 yr. male, p4). (Donors were different from those presented in Fig. 2) (PNG 1181 kb)

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High resolution image (TIF 4959 kb)
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Supplemental Fig. 3

Immunofluorescence analysis after neurogenic induction (NDM-C) for 21–35 days. Top panel: Oral stem cells including DPSCs, SCAP and GMSCs (GMSCs from A and B two donors). Bottom panel: Non-OSCs including BMMSCs, FFs and DFs. Genes tested included neural genes nestin, βIII-tubulin, NFM, Nav1.6 and CNPase. Scale bar: DPSCs, all 50 μm; SCAP, all 100 μm; GMSCs and BMMSCs, all 50 μm; DF, nestin, 100 μm; NFM, 200 μm; Nav1.6, 50 μm. (PNG 24206 kb)

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High resolution image (TIF 85149 kb)
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Supplemental Fig. 4

Neurosphere formation and differentiation of DPSCs (Method-1). Upper panel: (A, B) DPSC-derived neurospheres after 3 days cultured in NDM-1 stage-1. (C) Neural differentiation of DPSC-derived neurosphere on day 2 (NDM-1 stage-2). (D) After 6 days of neural differentiation (NDM-1 stage-2), fibroblast-like cells became confluent in the central area of neurospheres. Lower panel: A few cells with long processes could be seen in the peripheral area of neurospheres, while the cell bodies were not spheroidal. Immunofluorescence staining showing βIII-tubulin-positive cells (red). DAPI: nuclear stain. Mouse IgG serves as the negative control. Scale bar: all the scale bars are 100 μm, except in (D), 500 μm. (PNG 2241 kb)

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High resolution image (TIF 7361 kb)
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Supplementary Fig. 5

Neurogenesis of human DPSC neurospheres on low-attachment and adherent plates under low and normal oxygen conditions (Method-2). (A) Formation of primary (72 h) DPSC neurospheres under normoxic and hypoxic conditions at stage-1 (non-adherent images on left). Representative images of neurospheres cultured on adherent plates after 7 days (middle) and 12 days (right) with neurodifferentiation medium (stage-2). Similar cell morphological characteristics are observed in both normoxic and hypoxic plates. Scale bars: 100 μm. (B) Immunofluorescence analysis of neural markers. Cultured DPSC neurospheres were induced with neurodifferentiation media for 12 days under normoxic or hypoxic conditions. DAPI: nuclear stain; βIII-tubulin: neuronal-specific marker (green); GFAP: astrocyte-specific marker (red); Merged image with all three fields. Scale bars: 100 μm. (PNG 5173 kb)

12015_2018_9854_MOESM11_ESM.tif (38.3 mb)
High resolution image (TIF 39244 kb)
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Supplemental Fig. 6

Neurosphere-mediated neuronogenesis (Method-3) of human GMSCs. Neurospheres formed under neural induction stage for 6–8 days as the spheres increased in size over time (stage-1). Representative images of late phase (day 6). After which, spheres were seeded onto poly-l-ornithine/laminin coated glass coverslips or culture wells and stimulated under neural maturation medium for ~4 weeks (stage-2). The cells gradually showed spherical cell body and axon-like extensions over time. Representative images showing early phase (day 4) and late phase (day 28). Control: non-stimulated. Scale bars: Top panel, 500 μm (left 2 images,) 100 μm (right 2 images). Bottom panel, 100 μm (left 2 images), 50 μm (right 2 images). (PNG 4084 kb)

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High resolution image (TIF 17303 kb)
12015_2018_9854_MOESM13_ESM.mp4 (19.1 mb)
Supplemental Fig. 7 Neurosphere-mediated neuronogenesis (Method-3) of GMSCs. After stage-1 neurosphere step, the spheres were seeded onto wells of a 24-well plate under stage-2 NMM. Selected locations of the attached spheres were imaged consecutively starting at day 1 throughout the maturation period. The images were combined into a video format. Two locations each contains a single cell were traced (red and green boxes) backward from day 28 to day 1. From day 28 to 17, the same cell was recognized and traced. Days before the 17th day, the same cell was not easily recognized due to migration or crowdedness of cells. (MP4 19,552 kb)

References

  1. 1.
    Tondreau, T., Dejeneffe, M., Meuleman, N., Stamatopoulos, B., Delforge, A., Martiat, P., Bron, D., & Lagneaux, L. (2008). Gene expression pattern of functional neuronal cells derived from human bone marrow mesenchymal stromal cells. BMC Genomics, 9, 166.CrossRefGoogle Scholar
  2. 2.
    Shiota, M., Heike, T., Haruyama, M., Baba, S., Tsuchiya, A., Fujino, H., Kobayashi, H., Kato, T., Umeda, K., Yoshimoto, M., & Nakahata, T. (2007). Isolation and characterization of bone marrow-derived mesenchymal progenitor cells with myogenic and neuronal properties. Experimental Cell Research, 313, 1008–1023.CrossRefGoogle Scholar
  3. 3.
    Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S., & Marshak, D. R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147.CrossRefGoogle Scholar
  4. 4.
    Cho, K. J., Trzaska, K. A., Greco, S. J., McArdle, J., Wang, F. S., Ye, J. H., & Rameshwar, P. (2005). Neurons derived from human mesenchymal stem cells show synaptic transmission and can be induced to produce the neurotransmitter substance P by interleukin-1 alpha. Stem Cells, 23, 383–391.CrossRefGoogle Scholar
  5. 5.
    Greco, S. J., Zhou, C., Ye, J. H., & Rameshwar, P. (2007). An interdisciplinary approach and characterization of neuronal cells transdifferentiated from human mesenchymal stem cells. Stem Cells and Development, 16, 811–826.CrossRefGoogle Scholar
  6. 6.
    Sakai, K., Yamamoto, A., Matsubara, K., Nakamura, S., Naruse, M., Yamagata, M., Sakamoto, K., Tauchi, R., Wakao, N., Imagama, S., Hibi, H., Kadomatsu, K., Ishiguro, N., & Ueda, M. (2012). Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. The Journal of Clinical Investigation, 122, 80–90.Google Scholar
  7. 7.
    Hofstetter, C. P., Schwarz, E. J., Hess, D., Widenfalk, J., el Manira, A., Prockop, D. J., & Olson, L. (2002). Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proceedings of the National Academy of Sciences, 99, 2199–2204.CrossRefGoogle Scholar
  8. 8.
    Joyce, N., Annett, G., Wirthlin, L., Olson, S., Bauer, G., & Nolta, J. A. (2010). Mesenchymal stem cells for the treatment of neurodegenerative disease. Regenerative Medicine, 5, 933–946.CrossRefGoogle Scholar
  9. 9.
    Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Sudhof, T. C., & Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463, 1035–1041.CrossRefGoogle Scholar
  10. 10.
    Marro, S., Pang, Z. P., Yang, N., Tsai, M. C., Qu, K., Chang, H. Y., Südhof, T. C., & Wernig, M. (2011). Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell, 9, 374–382.CrossRefGoogle Scholar
  11. 11.
    Chai, Y., Jiang, X., Ito, Y., Bringas P Jr, Han, J., Rowitch, D. H., Soriano, P., McMahon, A., & Sucov, H. M. (2000). Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development, 127, 1671–1679.Google Scholar
  12. 12.
    Karaoz, E., Demircan, P. C., Saglam, O., Aksoy, A., Kaymaz, F., & Duruksu, G. (2011). Human dental pulp stem cells demonstrate better neural and epithelial stem cell properties than bone marrow-derived mesenchymal stem cells. Histochemistry and Cell Biology, 136, 455–473.CrossRefGoogle Scholar
  13. 13.
    Huang, G. T. J., Gronthos, S., & Shi, S. (2009). Mesenchymal stem cells derived from dental tissues vs. those from other sources: Their biology and role in regenerative medicine. Journal of Dental Research, 88, 792–806.CrossRefGoogle Scholar
  14. 14.
    Tang, L., Li, N., Xie, H., & Jin, Y. (2011). Characterization of mesenchymal stem cells from human normal and hyperplastic gingiva. Journal of Cellular Physiology, 226, 832–842.CrossRefGoogle Scholar
  15. 15.
    Morsczeck, C., Huang, G. T.-J., & Shi, S. (2013). Stem and progenitor cells of dental and gingival tissue origin. In G. T.-J. Huang & I. Thesleff (Eds.), Stem cells, craniofacial development and regeneration (1st ed., pp. 285–302). Hoboken: Wiley-Blackwell.CrossRefGoogle Scholar
  16. 16.
    Zhang, Q., Shi, S., Liu, Y., Uyanne, J., Shi, Y., & Le, A. D. (2009). Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. Journal of Immunology, 183, 7787–7798.CrossRefGoogle Scholar
  17. 17.
    Huang, G. T. J., Shagramanova, K., & Chan, S. W. (2006). Formation of odontoblast-like cells from cultured human dental pulp cells on dentin in vitro. Journal of Endodontia, 32, 1066–1073.CrossRefGoogle Scholar
  18. 18.
    Tomar, G. B., Srivastava, R. K., Gupta, N., Barhanpurkar, A. P., Pote, S. T., Jhaveri, H. M., Mishra, G. C., & Wani, M. R. (2010). Human gingiva-derived mesenchymal stem cells are superior to bone marrow-derived mesenchymal stem cells for cell therapy in regenerative medicine. Biochemical and Biophysical Research Communications, 393, 377–383.CrossRefGoogle Scholar
  19. 19.
    Arthur, A., Rychkov, G., Shi, S., Koblar, S. A., & Gronthos, S. (2008). Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells, 26, 1787–1795.CrossRefGoogle Scholar
  20. 20.
    Ebrahimi, B., Yaghoobi, M. M., Kamal-abadi, A. M., & Raoof, M. (2011). Human dental pulp stem cells express many pluripotency regulators and differentiate into neuronal cells. Neural Regeneration Research, 6, 2666–2672.Google Scholar
  21. 21.
    Aanismaa, R., Hautala, J., Vuorinen, A., Miettinen, S., & Narkilahti, S. (2012). Human dental pulp stem cells differentiate into neural precursors but not into mature functional neurons. Stem Cell Discovery, 2, 85–91.CrossRefGoogle Scholar
  22. 22.
    Gervois, P., Struys, T., Hilkens, P., Bronckaers, A., Ratajczak, J., Politis, C., Brône, B., Lambrichts, I., & Martens, W. (2015). Neurogenic maturation of human dental pulp stem cells following neurosphere generation induces morphological and electrophysiological characteristics of functional neurons. Stem Cells and Development, 24, 296–311.CrossRefGoogle Scholar
  23. 23.
    Huang, G. T. J., Yamaza, T., Shea, L. D., et al. (2009). 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, 16, 605–615.CrossRefGoogle Scholar
  24. 24.
    Al-Habib, M., Yu, Z., & Huang, G. T. (2013). Small molecules affect human dental pulp stem cell properties via multiple signaling pathways. Stem Cells and Development, 22, 2402–2413.CrossRefGoogle Scholar
  25. 25.
    Yan, X., Qin, H., Qu, C., Tuan, R. S., Shi, S., & Huang, G. T. (2010). iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells and Development, 19, 469–480.CrossRefGoogle Scholar
  26. 26.
    El Ayachi, I., Zhang, J., Zou, X. Y., et al. (2017). 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, 12, e1836–e1851.CrossRefGoogle Scholar
  27. 27.
    Yu, Z., Gauthier, P., Tran, Q. T., et al. (2015). Differential properties of human ALP+ periodontal ligament stem cells vs their ALP- counterparts. Journal of Stem Cell Research and Therapy, 5, 292.Google Scholar
  28. 28.
    Schmittgen, T. D., & Livak, K. J. (2008). Analyzing real-time PCR data by the comparative CT method. Nature Protocols, 3, 1101–1108.CrossRefGoogle Scholar
  29. 29.
    Zou, X. Y., Yang, H. Y., Yu, Z., Tan, X. B., Yan, X., & Huang, G. T. (2012). Establishment of transgene-free induced pluripotent stem cells reprogrammed from human stem cells of apical papilla for neural differentiation. Stem Cell Research & Therapy, 3, 43.CrossRefGoogle Scholar
  30. 30.
    Alongi, D. J., Yamaza, T., Song, Y., Fouad, A. F., Romberg, E. E., Shi, S., Tuan, R. S., & Huang, G. T. J. (2010). Stem/progenitor cells from inflamed human dental pulp retain tissue regeneration potential. Regenerative Medicine, 5, 617–631.CrossRefGoogle Scholar
  31. 31.
    Sonoyama, W., Liu, Y., Yamaza, T., Tuan, R. S., Wang, S., Shi, S., & Huang, G. T. J. (2008). Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: A pilot study. Journal of Endodontia, 34, 166–171.CrossRefGoogle Scholar
  32. 32.
    Djouad, F., Jackson, W. M., Bobick, B. E., Janjanin, S., Song, Y., Huang, G. T. J., & Tuan, R. S. (2010). Activin a expression regulates multipotency of mesenchymal progenitor cells. Stem Cell Research & Therapy, 1, 11.CrossRefGoogle Scholar
  33. 33.
    Lu, P., Blesch, A., & Tuszynski, M. H. (2004). Induction of bone marrow stromal cells to neurons: Differentiation, transdifferentiation, or artifact? Journal of Neuroscience Research, 77, 174–191.CrossRefGoogle Scholar
  34. 34.
    Abe, S., Yamaguchi, S., & Amagasa, T. (2007). Multilineage cells from apical pulp of human tooth with immature apex. Oral Science International, 4, 45–58.CrossRefGoogle Scholar
  35. 35.
    Jang, S., Cho, H. H., Cho, Y. B., Park, J. S., & Jeong, H. S. (2010). Functional neural differentiation of human adipose tissue-derived stem cells using bFGF and forskolin. BMC Cell Biology, 11, 25.CrossRefGoogle Scholar
  36. 36.
    Deleyrolle, L. P., & Reynolds, B. A. (2009). Isolation, expansion, and differentiation of adult mammalian neural stem and progenitor cells using the neurosphere assay. Methods in Molecular Biology, 549, 91–101.CrossRefGoogle Scholar
  37. 37.
    Louis, S. A., Mak, C. K., & Reynolds, B. A. (2013). Methods to culture, differentiate, and characterize neural stem cells from the adult and embryonic mouse central nervous system. Methods in Molecular Biology, 946, 479–506.CrossRefGoogle Scholar
  38. 38.
    Singec, I., Knoth, R., Meyer, R. P., Maciaczyk, J., Volk, B., Nikkhah, G., Frotscher, M., & Snyder, E. Y. (2006). Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology. Nature Methods, 3, 801–806.CrossRefGoogle Scholar
  39. 39.
    Pardal, R., Ortega-Saenz, P., Duran, R., & Lopez-Barneo, J. (2007). Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body. Cell, 131, 364–377.CrossRefGoogle Scholar
  40. 40.
    Morrison, S. J., Csete, M., Groves, A. K., Melega, W., Wold, B., & Anderson, D. J. (2000). Culture in reduced levels of oxygen promotes clonogenic sympathoadrenal differentiation by isolated neural crest stem cells. The Journal of Neuroscience, 20, 7370–7376.CrossRefGoogle Scholar
  41. 41.
    Rhee, Y. H., Choi, M., Lee, H. S., Park, C. H., Kim, S. M., Yi, S. H., Oh, S. M., Cha, H. J., Chang, M. Y., & Lee, S. H. (2013). Insulin concentration is critical in culturing human neural stem cells and neurons. Cell Death & Disease, 4, e766.CrossRefGoogle Scholar
  42. 42.
    Marynka-Kalmani, K., Treves, S., Yafee, M., Rachima, H., Gafni, Y., Cohen, M. A., & Pitaru, S. (2010). The lamina propria of adult human oral mucosa harbors a novel stem cell population. Stem Cells, 28, 984–995.Google Scholar
  43. 43.
    Luo, L., He, Y., Wang, X., et al. (2018). Potential roles of dental pulp stem cells in neural regeneration and repair. Stem Cells International, 2018, 1731289.Google Scholar
  44. 44.
    Yang, N., Ng, Y. H., Pang, Z. P., Sudhof, T. C., & Wernig, M. (2011). Induced neuronal cells: How to make and define a neuron. Cell Stem Cell, 9, 517–525.CrossRefGoogle Scholar
  45. 45.
    Hu, W., Qiu, B., Guan, W., Wang, Q., Wang, M., Li, W., Gao, L., Shen, L., Huang, Y., Xie, G., Zhao, H., Jin, Y., Tang, B., Yu, Y., Zhao, J., & Pei, G. (2015). Direct conversion of Normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell, 17, 204–212.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Dong Li
    • 1
  • Xiao-Ying Zou
    • 2
    • 3
  • Ikbale El-Ayachi
    • 1
  • Luis O. Romero
    • 4
  • Zongdong Yu
    • 1
  • Alejandro Iglesias-Linares
    • 1
    • 5
  • Julio F. Cordero-Morales
    • 4
  • George T.-J. Huang
    • 1
    • 3
    Email author
  1. 1.Department of Bioscience Research, College of DentistryUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Cariology, Endodontology and Operative Dentistry, School and Hospital of StomatologyPeking UniversityBeijingPeople’s Republic of China
  3. 3.Department of EndodonticsBoston University Henry M. Goldman School of Dental MedicineBostonUSA
  4. 4.Department of Physiology, College of MedicineUniversity of Tennessee Health Science CenterMemphisUSA
  5. 5.Department of Dental Clinical SpecialtiesComplutense University of Madrid, School of Dental MedicineMadridSpain

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