Journal of Periodontal and Implant Science

  • 제52권6호
  • /
  • Pages.437-454
  • /
  • 2022
  • /
  • 2093-2278(pISSN)
  • /
  • 2093-2286(eISSN)
대한치주과학회 (Korean Academy of Periodontology)
권호 표지
DOI QR코드

DOI QR Code

Dental-derived cells for regenerative medicine: stem cells, cell reprogramming, and transdifferentiation

  • Young-Dan Cho (Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital) ;
  • Kyoung-Hwa Kim (Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital) ;
  • Yong-Moo Lee (Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital) ;
  • Young Ku (Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital) ;
  • Yang-Jo Seol (Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital)
  • 투고 : 2021.07.14
  • 심사 : 2022.01.24
  • 발행 : 2022.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Embryonic stem cells have been a popular research topic in regenerative medicine owing to their pluripotency and applicability. However, due to the difficulty in harvesting them and their low yield efficiency, advanced cell reprogramming technology has been introduced as an alternative. Dental stem cells have entered the spotlight due to their regenerative potential and their ability to be obtained from biological waste generated after dental treatment. Cell reprogramming, a process of reverting mature somatic cells into stem cells, and transdifferentiation, a direct conversion between different cell types without induction of a pluripotent state, have helped overcome the shortcomings of stem cells and raised interest in their regenerative potential. Furthermore, the potential of these cells to return to their original cell types due to their epigenetic memory has reinforced the need to control the epigenetic background for successful management of cellular differentiation. Herein, we discuss all available sources of dental stem cells, the procedures used to obtain these cells, and their ability to differentiate into the desired cells. We also introduce the concepts of cell reprogramming and transdifferentiation in terms of genetics and epigenetics, including DNA methylation, histone modification, and non-coding RNA. Finally, we discuss a novel therapeutic avenue for using dental-derived cells as stem cells, and explain cell reprogramming and transdifferentiation, which are used in regenerative medicine and tissue engineering.

키워드

과제정보

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. NRF-2020R1A2C1007536/2020R1C1C1005830).

참고문헌

  1. Zakrzewski W, Dobrzynski M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther 2019;10:68.
  2. Riveiro AR, Brickman JM. From pluripotency to totipotency: an experimentalist's guide to cellular potency. Development 2020;147:dev189845.
  3. Choumerianou DM, Dimitriou H, Kalmanti M. Stem cells: promises versus limitations. Tissue Eng Part B Rev 2008;14:53-60. https://doi.org/10.1089/teb.2007.0216
  4. Kuroda Y, Kitada M, Wakao S, Nishikawa K, Tanimura Y, Makinoshima H, et al. Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci U S A 2010;107:8639-43. https://doi.org/10.1073/pnas.0911647107
  5. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A 2000;97:13625-30. https://doi.org/10.1073/pnas.240309797
  6. Patel M, Yang S. Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell Rev Rep 2010;6:367-80. https://doi.org/10.1007/s12015-010-9123-8
  7. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663-76. https://doi.org/10.1016/j.cell.2006.07.024
  8. Waddington CH. The strategy of the genes. A discussion of some aspects of theoretical biology. London: George Allen & Unwin, Ltd; 1957.
  9. Ladewig J, Koch P, Brustle O. Leveling Waddington: the emergence of direct programming and the loss of cell fate hierarchies. Nat Rev Mol Cell Biol 2013;14:225-36. https://doi.org/10.1038/nrm3543
  10. Baum BJ, Mooney DJ. The impact of tissue engineering on dentistry. J Am Dent Assoc 2000;131:309-18. https://doi.org/10.14219/jada.archive.2000.0174
  11. Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A 2003;100:5807-12. https://doi.org/10.1073/pnas.0937635100
  12. Karaoz E, Dogan BN, Aksoy A, Gacar G, Akyuz S, Ayhan S, et al. Isolation and in vitro characterisation of dental pulp stem cells from natal teeth. Histochem Cell Biol 2010;133:95-112. https://doi.org/10.1007/s00418-009-0646-5
  13. Huang AH, Chen YK, Lin LM, Shieh TY, Chan AW. Isolation and characterization of dental pulp stem cells from a supernumerary tooth. J Oral Pathol Med 2008;37:571-4. https://doi.org/10.1111/j.1600-0714.2008.00654.x
  14. Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, et al. Stem cell properties of human dental pulp stem cells. J Dent Res 2002;81:531-5. https://doi.org/10.1177/154405910208100806
  15. Liu L, Ling J, Wei X, Wu L, Xiao Y. Stem cell regulatory gene expression in human adult dental pulp and periodontal ligament cells undergoing odontogenic/osteogenic differentiation. J Endod 2009;35:1368-76. https://doi.org/10.1016/j.joen.2009.07.005
  16. Iohara K, Zheng L, Ito M, Tomokiyo A, Matsushita K, Nakashima M. Side population cells isolated from porcine dental pulp tissue with self-renewal and multipotency for dentinogenesis, chondrogenesis, adipogenesis, and neurogenesis. Stem Cells 2006;24:2493-503. https://doi.org/10.1634/stemcells.2006-0161
  17. Zhang W, Walboomers XF, Van Kuppevelt TH, Daamen WF, Van Damme PA, Bian Z, et al. In vivo evaluation of human dental pulp stem cells differentiated towards multiple lineages. J Tissue Eng Regen Med 2008;2:117-25. https://doi.org/10.1002/term.71
  18. Govindasamy V, Abdullah AN, Ronald VS, Musa S, Ab Aziz ZA, Zain RB, et al. Inherent differential propensity of dental pulp stem cells derived from human deciduous and permanent teeth. J Endod 2010;36:1504-15.
  19. Gancheva MR, Kremer KL, Gronthos S, Koblar SA. Using dental pulp stem cells for stroke therapy. Front Neurol 2019;10:422.
  20. Shi S, Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 2003;18:696-704. https://doi.org/10.1359/jbmr.2003.18.4.696
  21. Liu L, Wei X, Ling J, Wu L, Xiao Y. Expression pattern of Oct-4, Sox2, and c-Myc in the primary culture of human dental pulp derived cells. J Endod 2011;37:466-72. https://doi.org/10.1016/j.joen.2010.12.012
  22. Pisciotta A, Bertoni L, Riccio M, Mapelli J, Bigiani A, La Noce M, et al. Use of a 3D floating sphere culture system to maintain the neural crest-related properties of human dental pulp stem cells. Front Physiol 2018;9:547.
  23. Gervois P, Struys T, Hilkens P, Bronckaers A, Ratajczak J, Politis C, et al. Neurogenic maturation of human dental pulp stem cells following neurosphere generation induces morphological and electrophysiological characteristics of functional neurons. Stem Cells Dev 2015;24:296-311. https://doi.org/10.1089/scd.2014.0117
  24. Arthur A, Shi S, Zannettino AC, Fujii N, Gronthos S, Koblar SA. Implanted adult human dental pulp stem cells induce endogenous axon guidance. Stem Cells 2009;27:2229-37. https://doi.org/10.1002/stem.138
  25. Govindasamy V, Ronald VS, Abdullah AN, Nathan KR, Ab Aziz ZA, Abdullah M, et al. Differentiation of dental pulp stem cells into islet-like aggregates. J Dent Res 2011;90:646-52. https://doi.org/10.1177/0022034510396879
  26. Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004;364:149-55. https://doi.org/10.1016/S0140-6736(04)16627-0
  27. Zhu W, Liang M. Periodontal ligament stem cells: current status, concerns, and future prospects. Stem Cells Int 2015;2015:972313.
  28. Lee JS, An SY, Kwon IK, Heo JS. Transdifferentiation of human periodontal ligament stem cells into pancreatic cell lineage. Cell Biochem Funct 2014;32:605-11. https://doi.org/10.1002/cbf.3057
  29. Ng TK, Yung JS, Choy KW, Cao D, Leung CK, Cheung HS, et al. Transdifferentiation of periodontal ligament-derived stem cells into retinal ganglion-like cells and its microRNA signature. Sci Rep 2015;5:16429.
  30. Nakamura S, Yamada Y, Katagiri W, Sugito T, Ito K, Ueda M. Stem cell proliferation pathways comparison between human exfoliated deciduous teeth and dental pulp stem cells by gene expression profile from promising dental pulp. J Endod 2009;35:1536-42. https://doi.org/10.1016/j.joen.2009.07.024
  31. Martinez Saez D, Sasaki RT, Neves AD, da Silva MC. Stem cells from human exfoliated deciduous teeth: a growing literature. Cells Tissues Organs 2016;202:269-80. https://doi.org/10.1159/000447055
  32. Seo BM, Sonoyama W, Yamaza T, Coppe C, Kikuiri T, Akiyama K, et al. SHED repair critical-size calvarial defects in mice. Oral Dis 2008;14:428-34. https://doi.org/10.1111/j.1601-0825.2007.01396.x
  33. Esmaeili A, Alifarja S, Nourbakhsh N, Talebi A. Messenger RNA expression patterns of neurotrophins during transdifferentiation of stem cells from human-exfoliated deciduous teeth into neural-like cells. Avicenna J Med Biotechnol 2014;6:21-6.
  34. Dogan A, Demirci S, Sahin F. In vitro differentiation of human tooth germ stem cells into endothelial- and epithelial-like cells. Cell Biol Int 2015;39:94-103. https://doi.org/10.1002/cbin.10357
  35. Morsczeck C, Gotz W, Schierholz J, Zeilhofer F, Kuhn U, Mohl C, et al. Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol 2005;24:155-65. https://doi.org/10.1016/j.matbio.2004.12.004
  36. Karamzadeh R, Baghaban Eslaminejad M, Sharifi-Zarchi A. Comparative in vitro evaluation of human dental pulp and follicle stem cell commitment. Cell J 2017;18:609-18.
  37. Yildirim S, Zibandeh N, Genc D, Ozcan EM, Goker K, Akkoc T. The comparison of the immunologic properties of stem cells isolated from human exfoliated deciduous teeth, dental pulp, and dental follicles. Stem Cells Int 2016;2016:4682875.
  38. Yokoi T, Saito M, Kiyono T, Iseki S, Kosaka K, Nishida E, et al. Establishment of immortalized dental follicle cells for generating periodontal ligament in vivo. Cell Tissue Res 2007;327:301-11.
  39. Xu QL, Furuhashi A, Zhang QZ, Jiang CM, Chang TH, Le AD. Induction of salivary gland-like cells from dental follicle epithelial cells. J Dent Res 2017;96:1035-43. https://doi.org/10.1177/0022034517711146
  40. Chen G, Chen J, Yang B, Li L, Luo X, Zhang X, et al. Combination of aligned PLGA/Gelatin electrospun sheets, native dental pulp extracellular matrix and treated dentin matrix as substrates for tooth root regeneration. Biomaterials 2015;52:56-70. https://doi.org/10.1016/j.biomaterials.2015.02.011
  41. Genc D, Zibandeh N, Nain E, Arig u, Goker K, Aydiner EK, et al. IFN-γ stimulation of dental follicle mesenchymal stem cells modulates immune response of CD4+ T lymphocytes in Der p1+ asthmatic patients in vitro. Allergol Immunopathol (Madr) 2019;47:467-76. https://doi.org/10.1016/j.aller.2018.12.005
  42. Sonoyama W, Liu Y, Fang D, Yamaza T, Seo BM, Zhang C, et al. Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS One 2006;1:e79.
  43. Ikeda E, Hirose M, Kotobuki N, Shimaoka H, Tadokoro M, Maeda M, et al. Osteogenic differentiation of human dental papilla mesenchymal cells. Biochem Biophys Res Commun 2006;342:1257-62. https://doi.org/10.1016/j.bbrc.2006.02.101
  44. Zhang W, Zhang X, Li J, Zheng J, Hu X, Xu M, et al. Foxc2 and BMP2 induce osteogenic/odontogenic differentiation and mineralization of human stem cells from apical papilla. Stem Cells Int 2018;2018:2363917.
  45. Wang J, Liu B, Gu S, Liang J. Effects of Wnt/β-catenin signalling on proliferation and differentiation of apical papilla stem cells. Cell Prolif 2012;45:121-31. https://doi.org/10.1111/j.1365-2184.2012.00806.x
  46. Feng X, Huang D, Lu X, Feng G, Xing J, Lu J, et al. Insulin-like growth factor 1 can promote proliferation and osteogenic differentiation of human dental pulp stem cells via mTOR pathway. Dev Growth Differ 2014;56:615-24. https://doi.org/10.1111/dgd.12179
  47. Jiang Q, Du J, Yin X, Shan Z, Ma Y, Ma P, et al. Shh signaling, negatively regulated by BMP signaling, inhibits the osteo/dentinogenic differentiation potentials of mesenchymal stem cells from apical papilla. Mol Cell Biochem 2013;383:85-93. https://doi.org/10.1007/s11010-013-1757-9
  48. Li G, Han N, Yang H, Wang L, Lin X, Diao S, et al. Homeobox C10 inhibits the osteogenic differentiation potential of mesenchymal stem cells. Connect Tissue Res 2018;59:201-11.
  49. Wang Y, Pang X, Wu J, Jin L, Yu Y, Gobin R, et al. MicroRNA hsa-let-7b suppresses the odonto/osteogenic differentiation capacity of stem cells from apical papilla by targeting MMP1. J Cell Biochem 2018;119:6545-54.
  50. Marynka-Kalmani K, Treves S, Yafee M, Rachima H, Gafni Y, Cohen MA, et al. The lamina propria of adult human oral mucosa harbors a novel stem cell population. Stem Cells 2010;28:984-95. https://doi.org/10.1002/stem.425
  51. Izumi K, Tobita T, Feinberg SE. Isolation of human oral keratinocyte progenitor/stem cells. J Dent Res 2007;86:341-6.
  52. Tomar GB, Srivastava RK, Gupta N, Barhanpurkar AP, Pote ST, Jhaveri HM, et al. Human gingiva-derived mesenchymal stem cells are superior to bone marrow-derived mesenchymal stem cells for cell therapy in regenerative medicine. Biochem Biophys Res Commun 2010;393:377-83. https://doi.org/10.1016/j.bbrc.2010.01.126
  53. Rodriguez-Lozano FJ, Insausti CL, Iniesta F, Blanquer M, Ramirez MD, Meseguer L, et al. Mesenchymal dental stem cells in regenerative dentistry. Med Oral Patol Oral Cir Bucal 2012;17:e1062-7.
  54. Egusa H, Sonoyama W, Nishimura M, Atsuta I, Akiyama K. Stem cells in dentistry--part I: stem cell sources. J Prosthodont Res 2012;56:151-65. https://doi.org/10.1016/j.jpor.2012.06.001
  55. Han J, Okada H, Takai H, Nakayama Y, Maeda T, Ogata Y. Collection and culture of alveolar bone marrow multipotent mesenchymal stromal cells from older individuals. J Cell Biochem 2009;107:1198-204. https://doi.org/10.1002/jcb.22224
  56. Donovan MG, Dickerson NC, Hellstein JW, Hanson LJ. Autologous calvarial and iliac onlay bone grafts in miniature swine. J Oral Maxillofac Surg 1993;51:898-903. https://doi.org/10.1016/S0278-2391(10)80112-0
  57. Crespi R, Vinci R, Cappare P, Gherlone E, Romanos GE. Calvarial versus iliac crest for autologous bone graft material for a sinus lift procedure: a histomorphometric study. Int J Oral Maxillofac Implants 2007;22:527-32.
  58. Igarashi A, Segoshi K, Sakai Y, Pan H, Kanawa M, Higashi Y, et al. Selection of common markers for bone marrow stromal cells from various bones using real-time RT-PCR: effects of passage number and donor age. Tissue Eng 2007;13:2405-17. https://doi.org/10.1089/ten.2006.0340
  59. Song L, Tuan RS. Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. FASEB J 2004;18:980-2. https://doi.org/10.1096/fj.03-1100fje
  60. Lymperi S, Ligoudistianou C, Taraslia V, Kontakiotis E, Anastasiadou E. Dental stem cells and their applications in dental tissue engineering. Open Dent J 2013;7:76-81. https://doi.org/10.2174/1874210601307010076
  61. Young FI, Telezhkin V, Youde SJ, Langley MS, Stack M, Kemp PJ, et al. Clonal heterogeneity in the neuronal and glial differentiation of dental pulp stem/progenitor cells. Stem Cells Int 2016;2016:1290561.
  62. Leong WK, Henshall TL, Arthur A, Kremer KL, Lewis MD, Helps SC, et al. Human adult dental pulp stem cells enhance poststroke functional recovery through non-neural replacement mechanisms. Stem Cells Transl Med 2012;1:177-87. https://doi.org/10.5966/sctm.2011-0039
  63. Mead B, Logan A, Berry M, Leadbeater W, Scheven BA. Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury. Invest Ophthalmol Vis Sci 2013;54:7544-56.
  64. Gandia C, Arminan A, Garcia-Verdugo JM, Lledo E, Ruiz A, Minana MD, et al. Human dental pulp stem cells improve left ventricular function, induce angiogenesis, and reduce infarct size in rats with acute myocardial infarction. Stem Cells 2008;26:638-45. https://doi.org/10.1634/stemcells.2007-0484
  65. Yang R, Chen M, Lee CH, Yoon R, Lal S, Mao JJ. Clones of ectopic stem cells in the regeneration of muscle defects in vivo. PLoS One 2010;5:e13547.
  66. Annibali S, Bellavia D, Ottolenghi L, Cicconetti A, Cristalli MP, Quaranta R, et al. Micro-CT and PET analysis of bone regeneration induced by biodegradable scaffolds as carriers for dental pulp stem cells in a rat model of calvarial "critical size" defect: preliminary data. J Biomed Mater Res B Appl Biomater 2014;102:815-25. https://doi.org/10.1002/jbm.b.33064
  67. d'Aquino R, De Rosa A, Lanza V, Tirino V, Laino L, Graziano A, et al. Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur Cell Mater 2009;18:75-83. https://doi.org/10.22203/eCM.v018a07
  68. Nakashima M, Iohara K, Murakami M, Nakamura H, Sato Y, Ariji Y, et al. Pulp regeneration by transplantation of dental pulp stem cells in pulpitis: a pilot clinical study. Stem Cell Res Ther 2017;8:61.
  69. Feng F, Akiyama K, Liu Y, Yamaza T, Wang TM, Chen JH, et al. Utility of PDL progenitors for in vivo tissue regeneration: a report of 3 cases. Oral Dis 2010;16:20-8. https://doi.org/10.1111/j.1601-0825.2009.01593.x
  70. Iwata T, Yamato M, Washio K, Yoshida T, Tsumanuma Y, Yamada A, et al. Periodontal regeneration with autologous periodontal ligament-derived cell sheets - A safety and efficacy study in ten patients. Regen Ther 2018;9:38-44.
  71. Koseoglu S, Duran I, Saglam M, Bozkurt SB, Kirtiloglu OS, Hakki SS. Efficacy of collagen membrane seeded with autologous gingival fibroblasts in gingival recession treatment: a randomized, controlled pilot study. J Periodontol 2013;84:1416-24. https://doi.org/10.1902/jop.2012.120529
  72. Milinkovic I, Aleksic Z, Jankovic S, Popovic O, Bajic M, Cakic S, et al. Clinical application of autologous fibroblast cell culture in gingival recession treatment. J Periodontal Res 2015;50:363-70. https://doi.org/10.1111/jre.12215
  73. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861-72. https://doi.org/10.1016/j.cell.2007.11.019
  74. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;318:1917-20. https://doi.org/10.1126/science.1151526
  75. Tamaoki N, Takahashi K, Tanaka T, Ichisaka T, Aoki H, Takeda-Kawaguchi T, et al. Dental pulp cells for induced pluripotent stem cell banking. J Dent Res 2010;89:773-8. https://doi.org/10.1177/0022034510366846
  76. Miyoshi K, Tsuji D, Kudoh K, Satomura K, Muto T, Itoh K, et al. Generation of human induced pluripotent stem cells from oral mucosa. J Biosci Bioeng 2010;110:345-50. https://doi.org/10.1016/j.jbiosc.2010.03.004
  77. Wada N, Wang B, Lin NH, Laslett AL, Gronthos S, Bartold PM. Induced pluripotent stem cell lines derived from human gingival fibroblasts and periodontal ligament fibroblasts. J Periodontal Res 2011;46:438-47. https://doi.org/10.1111/j.1600-0765.2011.01358.x
  78. Yan X, Qin H, Qu C, Tuan RS, Shi S, Huang GT. iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells Dev 2010;19:469-80. https://doi.org/10.1089/scd.2009.0314
  79. Otsu K, Kishigami R, Oikawa-Sasaki A, Fukumoto S, Yamada A, Fujiwara N, et al. Differentiation of induced pluripotent stem cells into dental mesenchymal cells. Stem Cells Dev 2012;21:1156-64. https://doi.org/10.1089/scd.2011.0210
  80. Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier LS, et al. Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 2008;118:507-17. https://doi.org/10.1161/CIRCULATIONAHA.108.778795
  81. Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 2009;104:e30-41.
  82. Rufaihah AJ, Huang NF, Jame S, Lee JC, Nguyen HN, Byers B, et al. Endothelial cells derived from human iPSCS increase capillary density and improve perfusion in a mouse model of peripheral arterial disease. Arterioscler Thromb Vasc Biol 2011;31:e72-9.
  83. Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A 2008;105:5856-61. https://doi.org/10.1073/pnas.0801677105
  84. Tsuji O, Miura K, Okada Y, Fujiyoshi K, Mukaino M, Nagoshi N, et al. Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci U S A 2010;107:12704-9. https://doi.org/10.1073/pnas.0910106107
  85. Hargus G, Cooper O, Deleidi M, Levy A, Lee K, Marlow E, et al. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci U S A 2010;107:15921-6. https://doi.org/10.1073/pnas.1010209107
  86. Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 2009;19:429-38. https://doi.org/10.1038/cr.2009.28
  87. Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci U S A 2010;107:13426-31. https://doi.org/10.1073/pnas.1007884107
  88. Jeon OH, Panicker LM, Lu Q, Chae JJ, Feldman RA, Elisseeff JH. Human iPSC-derived osteoblasts and osteoclasts together promote bone regeneration in 3D biomaterials. Sci Rep 2016;6:26761.
  89. Zhu H, Kimura T, Swami S, Wu JY. Pluripotent stem cells as a source of osteoblasts for bone tissue regeneration. Biomaterials 2019;196:31-45. https://doi.org/10.1016/j.biomaterials.2018.02.009
  90. Zujur D, Kanke K, Onodera S, Tani S, Lai J, Azuma T, et al. Stepwise strategy for generating osteoblasts from human pluripotent stem cells under fully defined xeno-free conditions with small-molecule inducers. Regen Ther 2020;14:19-31. https://doi.org/10.1016/j.reth.2019.12.010
  91. Kidwai F, Mui BW, Arora D, Iqbal K, Hockaday M, de Castro Diaz LF, et al. Lineage-specific differentiation of osteogenic progenitors from pluripotent stem cells reveals the FGF1-RUNX2 association in neural crest-derived osteoprogenitors. Stem Cells 2020;38:1107-23. https://doi.org/10.1002/stem.3206
  92. Cieslar-Pobuda A, Knoflach V, Ringh MV, Stark J, Likus W, Siemianowicz K, et al. Transdifferentiation and reprogramming: overview of the processes, their similarities and differences. Biochim Biophys Acta Mol Cell Res 2017;1864:1359-69. https://doi.org/10.1016/j.bbamcr.2017.04.017
  93. Vaskova EA, Stekleneva AE, Medvedev SP, Zakian SM. "Epigenetic memory" phenomenon in induced pluripotent stem cells. Acta Naturae 2013;5:15-21. https://doi.org/10.32607/20758251-2013-5-4-15-21
  94. D'Urso A, Brickner JH. Mechanisms of epigenetic memory. Trends Genet 2014;30:230-6. https://doi.org/10.1016/j.tig.2014.04.004
  95. Ferguson-Smith AC. Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev Genet 2011;12:565-75. https://doi.org/10.1038/nrg3032
  96. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 2009;27:351-7.
  97. Jin B, Li Y, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer 2011;2:607-17.
  98. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011;21:381-95. https://doi.org/10.1038/cr.2011.22
  99. Wei JW, Huang K, Yang C, Kang CS. Non-coding RNAs as regulators in epigenetics (review). Oncol Rep 2017;37:3-9.
  100. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet 2007;8:253-62. https://doi.org/10.1038/nrg2045
  101. Eguchi G. Cellular and molecular background of wolffian lens regeneration. Cell Differ Dev 1988;25 Suppl:147-58. https://doi.org/10.1016/0922-3371(88)90111-6
  102. Echeverri K, Tanaka EM. Ectoderm to mesoderm lineage switching during axolotl tail regeneration. Science 2002;298:1993-6. https://doi.org/10.1126/science.1077804
  103. Arminan A, Gandia C, Bartual M, Garcia-Verdugo JM, Lledo E, Mirabet V, et al. Cardiac differentiation is driven by NKX2.5 and GATA4 nuclear translocation in tissue-specific mesenchymal stem cells. Stem Cells Dev 2009;18:907-18.
  104. Ellis KM, O'Carroll DC, Lewis MD, Rychkov GY, Koblar SA. Neurogenic potential of dental pulp stem cells isolated from murine incisors. Stem Cell Res Ther 2014;5:30.
  105. Nakatsuka R, Nozaki T, Uemura Y, Matsuoka Y, Sasaki Y, Shinohara M, et al. 5-Aza-2'-deoxycytidine treatment induces skeletal myogenic differentiation of mouse dental pulp stem cells. Arch Oral Biol 2010;55:350-7. https://doi.org/10.1016/j.archoralbio.2010.03.003
  106. Janebodin K, Zeng Y, Buranaphatthana W, Ieronimakis N, Reyes M. VEGFR2-dependent angiogenic capacity of pericyte-like dental pulp stem cells. J Dent Res 2013;92:524-31. https://doi.org/10.1177/0022034513485599
  107. Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell 2004;117:663-76. https://doi.org/10.1016/S0092-8674(04)00419-2
  108. Miskinyte G, Devaraju K, Gronning Hansen M, Monni E, Tornero D, Woods NB, et al. Direct conversion of human fibroblasts to functional excitatory cortical neurons integrating into human neural networks. Stem Cell Res Ther 2017;8:207.
  109. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 2010;142:375-86. https://doi.org/10.1016/j.cell.2010.07.002
  110. Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 2011;475:386-9. https://doi.org/10.1038/nature10116
  111. Hussein SM, Nagy AA. Progress made in the reprogramming field: new factors, new strategies and a new outlook. Curr Opin Genet Dev 2012;22:435-43. https://doi.org/10.1016/j.gde.2012.08.007
  112. Xu J, Du Y, Deng H. Direct lineage reprogramming: strategies, mechanisms, and applications. Cell Stem Cell 2015;16:119-34.
  113. Koche RP, Smith ZD, Adli M, Gu H, Ku M, Gnirke A, et al. Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 2011;8:96-105. https://doi.org/10.1016/j.stem.2010.12.001
  114. Tonge PD, Corso AJ, Monetti C, Hussein SM, Puri MC, Michael IP, et al. Divergent reprogramming routes lead to alternative stem-cell states. Nature 2014;516:192-7. https://doi.org/10.1038/nature14047
  115. Onder TT, Kara N, Cherry A, Sinha AU, Zhu N, Bernt KM, et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature 2012;483:598-602. https://doi.org/10.1038/nature10953
  116. Bueno-Costa A, Pineyro D, Soler M, Javierre BM, Raurell-Vila H, Subirana-Granes M, et al. B-cell leukemia transdifferentiation to macrophage involves reconfiguration of DNA methylation for long-range regulation. Leukemia 2020;34:1158-62. https://doi.org/10.1038/s41375-019-0643-1
  117. Cho YD, Bae HS, Lee DS, Yoon WJ, Woo KM, Baek JH, et al. Epigenetic priming confers direct cell transdifferentiation from adipocyte to osteoblast in a transgene-free state. J Cell Physiol 2016;231:1484-94. https://doi.org/10.1002/jcp.25183
  118. Cho Y, Kim B, Bae H, Kim W, Baek J, Woo K, et al. Direct gingival fibroblast/osteoblast transdifferentiation via epigenetics. J Dent Res 2017;96:555-61. https://doi.org/10.1177/0022034516686745
  119. Zhao Y, Londono P, Cao Y, Sharpe EJ, Proenza C, O'Rourke R, et al. High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun 2015;6:8243.
  120. Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 2011;13:215-22. https://doi.org/10.1038/ncb2164
  121. Yoo AS, Staahl BT, Chen L, Crabtree GR. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 2009;460:642-6. https://doi.org/10.1038/nature08139
  122. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 2011;476:228-31. https://doi.org/10.1038/nature10323
  123. Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C, Deng PY, et al. Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts. Neuron 2014;84:311-23. https://doi.org/10.1016/j.neuron.2014.10.016
  124. Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, et al. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 2011;9:113-8. https://doi.org/10.1016/j.stem.2011.07.002
  125. Takahashi T. Overexpression of Runx2 and MKP-1 stimulates transdifferentiation of 3T3-L1 preadipocytes into bone-forming osteoblasts in vitro. Calcif Tissue Int 2011;88:336-47. https://doi.org/10.1007/s00223-011-9461-9
  126. Huang P, Zhang L, Gao Y, He Z, Yao D, Wu Z, et al. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 2014;14:370-84. https://doi.org/10.1016/j.stem.2014.01.003
  127. Tanabe K, Ang CE, Chanda S, Olmos VH, Haag D, Levinson DF, et al. Transdifferentiation of human adult peripheral blood T cells into neurons. Proc Natl Acad Sci U S A 2018;115:6470-5. https://doi.org/10.1073/pnas.1720273115
  128. Chakraborty S, Ji H, Kabadi AM, Gersbach CA, Christoforou N, Leong KW. A CRISPR/Cas9-based system for reprogramming cell lineage specification. Stem Cell Reports 2014;3:940-7. https://doi.org/10.1016/j.stemcr.2014.09.013
  129. Wang C, Liu W, Nie Y, Qaher M, Horton HE, Yue F, et al. Loss of MyoD Promotes Fate Transdifferentiation of Myoblasts Into Brown Adipocytes. EBioMedicine 2017;16:212-23. https://doi.org/10.1016/j.ebiom.2017.01.015
  130. Kaur K, Yang J, Eisenberg CA, Eisenberg LM. 5-azacytidine promotes the transdifferentiation of cardiac cells to skeletal myocytes. Cell Reprogram 2014;16:324-30. https://doi.org/10.1089/cell.2014.0021
  131. Sayed N, Wong WT, Ospino F, Meng S, Lee J, Jha A, et al. Transdifferentiation of human fibroblasts to endothelial cells: role of innate immunity. Circulation 2015;131:300-9. https://doi.org/10.1161/CIRCULATIONAHA.113.007394