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VOLUME 20 , ISSUE 8 ( August, 2019 ) > List of Articles

REVIEW ARTICLE

Salivary Gland Stem Cells and Tissue Regeneration: An Update on Possible Therapeutic Application

Aikaterini Mitroulia, Marianna Gavriiloglou, Poluxeni Athanasiadou, Athina Bakopoulou, Athanasios Poulopoulos, Dimitrios Andreadis

Keywords : Salivary gland stem cells, Stem cell therapy, Tissue regeneration

Citation Information : Mitroulia A, Gavriiloglou M, Athanasiadou P, Bakopoulou A, Poulopoulos A, Andreadis D. Salivary Gland Stem Cells and Tissue Regeneration: An Update on Possible Therapeutic Application. J Contemp Dent Pract 2019; 20 (8):978-986.

DOI: 10.5005/jp-journals-10024-2620

License: CC BY-NC 4.0

Published Online: 01-04-2019

Copyright Statement:  Copyright © 2019; The Author(s).


Abstract

The aim of this review is to combine literature and experimental data concerning the impact of salivary gland (SG) stem cells (SCs) and their therapeutic prospects in tissue regeneration. So far, SCs were isolated from human and rodent major and minor SGs that enabled their regeneration. Several scaffolds were also combined with “SCs” and different “proteins” to achieve guided differentiation, although none have been proven as ideal. A new aspect of SC therapy aims to establish a vice versa relationship between SG and other ecto- or endodermal organs such as the pancreas, liver, kidneys, and thyroid. SC therapy could be a cheap and simple, non-traumatic, and individualized therapy for medically challenging cases like xerostomia and major organ failures. Functional improvement has been achieved in these organs, but till date, the whole organ in vivo regeneration was not achieved. Concerns about malignant formations and possible failures are yet to be resolved. In this review article, we highlight the basic embryology of SGs, existence of SG SCs with a detailed exploration of various cellular markers, scaffolds for tissue engineering, and, in the later part, cover potential therapeutic applications with a special focus on the pancreas and liver.


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  1. Tanasiewicz M, Tomasz Hildebrandt T, et al. Xerostomia of Various Etiologies:A Review of the Literature. Adv Clin Exp Med 2016;25: 199–206. DOI: 10.17219/acem/29375.
  2. Ivanovski K, Naumovski V, et al. Xerostomia and salivary levels of glucose and urea in patients with diabetes Prilozi. Prilozi 2012;33: 219–229.
  3. Holmberg KV, Hoffman MP. Anatomy, biogenesis and regeneration of salivary glands. Hoffman Monogr Oral Sci 2014;24:1–13.
  4. Zhang C, Li Y, et al. Therapeutic potential of human minor salivary gland epithelial progenitor cells in liver regeneration. Sci Rep 2017;7:12707. DOI: 10.1038/s41598-017-11880-z.
  5. Okumura K, Nakamura K, et al. Salivary Gland Progenitor Cells Induced by Duct Ligation Differentiate Into Hepatic and Pancreatic lineages. Hepatology 2003;38:104–113. DOI: 10.1053/jhep.2003.50259.
  6. Weissman IL. Stem Cells: Units of Development, Units of Regeneration, and Units in Evolution. Cell 2000;100:157–168. DOI: 10.1016/S0092-8674(00)81692-X.
  7. Wagers AJ, Weissman IL. Plasticity of Adult Stem Cells. Cell 2004;116:639–648. DOI: 10.1016/S0092-8674(04)00208-9.
  8. Pringle S, Van Os R, et al. Concise review: Adult salivary gland stem cells and a potential therapy for xerostomia. Stem Cells 2013;31: 613–619. DOI: 10.1002/stem.1327.
  9. Okumura K, Shinohara M, et al. Capability of Tissue Stem Cells to Organize into Salivary Rudiments. Stem Cells Int 2012;2012:502136. DOI: 10.1155/2012/502136.
  10. Aure MH, Arany S, et al. Salivary Glands, Stem Cells, Self-duplication, or Both? J Dent Res 2015;94:1502–1507. DOI: 10.1177/0022034515599770.
  11. Zhang H, Boddupally K, et al. Defining the Localization and Molecular Characteristic of Minor Salivary Gland Label-Retaining Cells. Stem Cells 2014;32:2267–2277. DOI: 10.1002/stem.1715.
  12. Andreadis D, Bakopoulou A, et al. Minor salivary glands of the lips: a novel, easily accessible source of potential stem/progenitor cells. Clin Oral Invest 2014;18:847–856. DOI: 10.1007/s00784-013-1056-6.
  13. ISBN: 9780323485180 eBook.
  14. Rothova M, Thompson H, et al. Lineage tracing of the endoderm during oral development. Dev Dyn 2012;241:1183–1191. DOI: 10.1002/dvdy.23804.
  15. Kimoto M, Yura Y, et al. Label retaining cells in rat submandibular gland. J Histochem Cytochem 2008;56:15–24. DOI: 10.1369/jhc.7A7269.2007.
  16. Lu L, Li Y, et al. Characterization of a Self-renewing and Multi-potent Cell Population Isolated from Human Minor Salivary Glands. Sci Rep 2015;5:10106. DOI: 10.1038/srep10106.
  17. Kwak M, Ninche N, et al. c-Kit+ Cells in Adult Salivary Glands do not Function as Tissue Stem Cells. Sci Rep 2018;8:14193. DOI: 10.1038/s41598-018-32557-1.
  18. Lombaert IM, Brunsting JF, et al. Rescue of Salivary gland function after stem cell transplantation in irradiated glands. PLoS One 2008;3:e2063. DOI: 10.1371/journal.pone.0002063.
  19. Lin SL. Concise review: deciphering the mechanism behind induced pluripotent stem cell generation. Stem Cells 2011;29:1645–1649. DOI: 10.1002/stem.744.
  20. Banh A, Xiao N, et al. A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell Enrichment In Vivo. Clin Cancer Res 2011;17:7265–7272. DOI: 10.1158/1078-0432.CCR-11-0179.
  21. Bullard T, Koek L, et al. Ascl3 expression marks a progenitor population of both acinar and ductal cells in mouse salivary glands. Dev Biol 2008;320:72–78. DOI: 10.1016/j.ydbio.2008.04.018.
  22. Patel VN, Hoffman MP. Salivary gland development: a template for regeneration. Semin Cell Dev Biol 2014;25-26:52–60. DOI: 10.1016/j.semcdb.2013.12.001.
  23. Yang TL, Young TH. The enhancement of submandibular gland branch formation on chitosan membrane. Biomaterials 2008;29(16): 2501–2508. DOI: 10.1016/j.biomaterials.2008.02.014.
  24. Cantara SI, Soscia DA, et al. Selective functionalization of nanofiber scaffolds to regulate SG epithelial cell proliferation and polarity. Biomaterials 2012;33:8372–8382. DOI: 10.1016/j.biomaterials.2012.08.021.
  25. Kleinman HK, Martin GR. Matrigel: basement membrane matrix with biological activity. Semin Cancer Biol 2005;15:378–386. DOI: 10.1016/j.semcancer.2005.05.004.
  26. Lombaert I, Movahednia MM, et al. Concise Review: Salivary Gland Regeneration: Therapeutic Approaches from Stem Cells to Tissue Organoids. Stem Cells 2017;35:97–105. DOI: 10.1002/stem.2455.
  27. Gao Z, Wu T, et al. Generation of Bioartificial salivary gland using whole organ decellularized Bioscaffold. Cells Tissues Organs 2014;200:171–180. DOI: 10.1159/000371873.
  28. Shin HS, Kook YM, et al. Functional spheroid organization of human salivary gland cells cultured on hydrogel-micropatterned nanofibrous microwells. Acta Biomater 2016;45:121–132. DOI: 10.1016/j.actbio.2016.08.058.
  29. Shubin AD, Felong TJ, et al. Development of poly (ethylene glycol) hydrogels for salivary gland tissue engineering applications. Tissue Eng Part A 2015;21:1733–1751. DOI: 10.1089/ten.tea. 2014.0674.
  30. Peters SB, Naim N, et al. Biocompatible Tissue Scaffold Compliance Promotes Salivary Gland Morphogenesis and Differentiation. Tissue Eng Part A 2014;20:1632–1642. DOI: 10.1089/ten.tea.2013.0515.
  31. Zhang BX, Zhang ZL, et al. Silk fibroin scaffolds promote formation of the ex vivo niche for salivary gland epithelial cell growth, matrix formation, and retention of differentiated function. Tissue Eng Part A 2015;21:1611–1620. DOI: 10.1089/ten.tea.2014.0411.
  32. Pradhan-Bhatt S, Harrington DA, et al. A Novel In Vivo Model for Evaluating Functional Restoration of a Tissue-Engineered Salivary Gland. Laryngoscope 2014;124:456–461. DOI: 10.1002/lary.24297.
  33. Sequeira SJ, Soscia DA, et al. The regulation of focal adhesion complex formation and salivary gland epithelial cell organization by nanofibrous PLGA scaffolds. Biomaterials 2012;33:3175–3186. DOI: 10.1016/j.biomaterials.2012.01.010.
  34. Ma B, Xie J, et al. Rational design of nanofiber scaffolds for orthopedic tissue repair and regeneration. Nanomedicine (Lond) 2013;8: 1459–1481. DOI: 10.2217/nnm.13.132.
  35. Obregon F, Vaquette C, et al. Three-dimensional bioprinting for regenerative dentistry and craniofacial tissue engineering. J Dent Res 2015;94:143S–152S. DOI: 10.1177/0022034515588885.
  36. Annabi N, Tamayol A, et al. 25th anniversary article: rational design and applications of hydrogels in regenerative medicine. Adv Mater 2014;26:85–124. DOI: 10.1002/adma.201303233.
  37. Amrollahi P, Shah B, et al. Recent advancements in regenerative dentistry: A review. Mater Sci Eng C Mater Biol Appl 2016;69: 1383–1390. DOI: 10.1016/j.msec.2016.08.045.
  38. Hutmacher DW, Sittinger M, et al. Scaffold-based tissue engineering: rationale for computer-aided design and solid free-form fabrication systems. Trends Biotechnol 2004;22:354–362. DOI: 10.1016/j.tibtech.2004.05.005.
  39. Sugito T, Kagami H, et al. Transplantation of cultured salivary gland cells into an atrophic salivary gland. Cell Transplant 2004;13:691–699. DOI: 10.3727/000000004783983567.
  40. Hisatomi Y, Okumura K, et al. Flow cytometric isolation of endodermal progenitors from mouse salivary gland differentiate into hepatic and pancreatic linerage. Hepatology 2004;39:667–675. DOI: 10.1002/hep.20063.
  41. Feng J, van der Zwaag M, et al. Isolation and characterization of human salivary gland cells for stem cell transplantation to reduce radiation-induced hyposalivation. Radiother Oncol 2009;92:466–471. DOI: 10.1016/j.radonc.2009.06.023.
  42. Kojima T, Kanemaru S, et al. Regeneration of radiation damaged salivary glands with adipose-derived stromal cells. Laryngoscope 2011;121:1864–1869. DOI: 10.1002/lary.22080.
  43. Lin CY, Chang FH, et al. Cell therapy for salivary gland regeneration. J Dent Res 2011;90:341–346. DOI: 10.1177/0022034510386374.
  44. Pringle S, Maimets M, et al. Human Salivary Gland Stem Cells Functionally Restore Radiation Damaged Salivary Glands. Stem Cells 2016;34:640–652. DOI: 10.1002/stem.2278.
  45. Grønhøj C, Jensen DH, et al. First-in-man mesenchymal stem cells for radiation-induced xerostomia (MESRIX): study protocol for a randomized controlled trial. Trials 2017;18:108. DOI: 10.1186/s13063-017-1856-0.
  46. Baum BJ, Alevizos I, et al. Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction. Proc Natl Acad Sci U S A 2012;109:19403–19407. DOI: 10.1073/pnas.1210662109.
  47. Alevizos I, Zheng C, et al. Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Gene Ther 2017;24:176–186. DOI: 10.1038/gt.2016.87.
  48. Zheng C, Cotrim AP, et al. Prevention of radiation induced salivary hypofunction following hKGF gene delivery to murine submandibular glands. Clin Cancer Res 2011;17:2842–2851. DOI: 10.1158/1078-0432.CCR-10-2982.
  49. Hai B, Yang Z, et al. Concurrent transient activation of Wnt/beta-catenin pathway prevents radiation damage to salivary glands. Int J Radiat Oncol Biol Phys 2012;83:e109–e116. DOI: 10.1016/j.ijrobp.2011.11.062.
  50. Arany S, Benoit DS, et al. Nanoparticle-mediated gene silencing confers radioprotection to salivary glands in vivo. Mol Ther 2013;21:1182–1194. DOI: 10.1038/mt.2013.42.
  51. Patel VN, Lombaert IM, et al. Hs3st3-modified heparan sulfate controls KIT1 progenitor expansion by regulating 3-O-sulfotransferases. Dev Cell 2014;29:662–673. DOI: 10.1016/j.devcel.2014.04.024.
  52. Neumann Y, David R, et al. Long-term cryopreservation model of rat salivary gland stem cells for future therapy in irradiated head and neck cancer patients. Tissue Eng Part C Methods 2012;18:710–718. DOI: 10.1089/ten.tec.2012.0013.
  53. Ogawa M, Oshima M, et al. Functional salivary gland regeneration by transplantation of a bioengineered organ germ. Nat Commun 2013;4:2498. DOI: 10.1038/ncomms3498.
  54. Lim JY, Yi T, et al. Intraglandular transplantation of bone marrow-derived clonal mesenchymal stem cells for amelioration of post-irradiation salivary gland damage. Oral Oncol 2013;49:136–143. DOI: 10.1016/j.oraloncology.2012.08.010.
  55. Kawakami M, Ishikawa H, et al. Functional transplantation of salivary gland cells differentiated from mouse early ES cells in vitro. Hum Cell 2013;26:80–90. DOI: 10.1007/s13577-013-0061-z.
  56. Ono H, Obana A, et al. Regenerating salivary glands in the microenvironment of induced pluripotent stem cells. Biomed Res Int 2015;2015:293570. DOI: 10.1155/2015/293570.
  57. Pradhan-Bhatt S, Harrington DA, et al. Implantable three-dimensional salivary spheroid assemblies demonstrate fluid and protein secretory responses to neurotransmitters. Tissue Eng Part A 2013;19:1610–1620. DOI: 10.1089/ten.tea.2012.0301.
  58. Pradhan S, Liu C, et al. Lumen formation in three dimensional cultures of salivary acinar cells. Otolaryngol Head Neck Surg 2010;142:191–195. DOI: 10.1016/j.otohns.2009.10.039.
  59. Sequeira SJ, Soscia DA, et al. The regulation of focal adhesion complex formation and salivary gland epithelial cell organization by nanofibrous PLGA scaffolds. Biomaterials 2012;33:3175–3186. DOI: 10.1016/j.biomaterials.2012.01.010.
  60. Nelson J, Manzella K, et al. Current cell models for bioengineering a salivary gland: a mini-review of emerging technologies. Oral Dis 2013;19:236–244. DOI: 10.1111/j.1601-0825.2012.01958.x.
  61. Dor Y, Brown J, et al. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004;429: 41–46. DOI: 10.1038/nature02520.
  62. Murtaugh LC, Kopinke D. Pancreatic stem cells StemBook. The Stem Cell Research Community, Stem Book, ed.: Schier AF. Last revised September 6, 2008. Published July 11, 2008.
  63. Bonner-Weir S, Toschi E, et al. The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes 2004; 5(Suppl 2):16–22. DOI: 10.1111/j.1399-543X.2004.00075.x.
  64. Strobel O, Rosow DE, et al. Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia. Gastroenterology 2010;138:1166–1177. DOI: 10.1053/j.gastro.2009.12.005.
  65. Wang Y, Lanzoni G, et al. Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis. Stem Cells 2013;31:1966–1979. DOI: 10.1002/stem.1460.
  66. Govindasamy V, Ronald VS, et al. Differentiation of dental pulp stem cells into islet-like aggregates. J Dent Res 2011;90:646–652. DOI: 10.1177/0022034510396879.
  67. Gorjupa E, Dannerb S, et al. Glandular tissue from human pancreas and salivary gland yields similar stem cell populations. Eur J Cell Biol 2009;88:409–421. DOI: 10.1016/j.ejcb.2009.02.187.
  68. Okumura K, Nakamura K, et al. Salivary Gland Progenitor Cells Induced by Duct Ligation Differentiate Into Hepatic and Pancreatic Lineages. Hepatology 2003;38:104–113. DOI: 10.1053/jhep.2003.50259.
  69. Sato A, Okumura K, et al. Isolation, tissue localization, and cellular characterization of progenitors derived from adult human salivary glands. Cloning Stem Cells 2007;9:191–205. DOI: 10.1089/clo.2006.0054.
  70. Baek H, Noh YH, et al. Autonomous isolation, long-term culture and differentiation potential of adult salivary gland-derived stem/progenitor cells. J Tissue Eng Regen Med 2014;8:717–727. DOI: 10.1002/term.1572.
  71. Michalopoulos GK. Liver regeneration. J Cellular Philosophy 2007;213:286–300. DOI: 10.1002/jcp.21172.
  72. Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 2003;120:117–130. DOI: 10.1016/S0925-4773(02)00338-6.
  73. Xiang S, Dong HH, et al. Oval cell response is attenuated by depletion of liverresidenr macrophages in the-2AAF/Partial hepatectomy rat. PLoS One 2012;7:e35180. DOI: 10.1371/journal.pone.0035180.
  74. Lagasse E, Connors H, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000;6:1229–1234. DOI: 10.1038/81326.
  75. Lanzoni G, Oikawa T, et al. Concise review: Clinical programs of stem cell therapies for liver and pancreas. Stem Cells 2013;31:2047–2060. DOI: 10.1002/stem.1457.
  76. Wang Y, Cui CB, et al. Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds. Hepatology 2011;53:293–305. DOI: 10.1002/hep.24012.
  77. Holtzinger A, Streeter PR, et al. New markers for tracking endoderm induction and hepatocyte differentiation from human pluripotent stem cells. Development 2015;142:4253–4265. DOI: 10.1242/dev.121020.
  78. Togarrati PP, Sasaki RT, et al. Identification and characterization of a rich population of CD34+ mesenchymal stem/stromal cells in human parotid, sublingual and submandibular glands. Sci Rep 2017;7:3484. DOI: 10.1038/s41598-017-03681-1.
  79. Sidney LE, Branch MJ, et al. Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells 2014;32: 1380–1389. DOI: 10.1002/stem.1661.
  80. Maria OM, Maria AM, et al. Cell surface markers CD44 and CD166 localized specific populations of salivary acinar cells. Oral Dis 2012;18:162–168. DOI: 10.1111/j.1601-0825.2011.01858.x.
  81. Jiang FX, Morahan G. Pancreatic stem cells remain unresolved. Stem Cells Dev 2014;23:2803–2812. DOI: 10.1089/scd.2014.0214.
  82. Weiss TS, Lichtenauer M, et al. Hepatic progenitor cells from adult human livers for cell transplantation. Gut 2008;57:1129–1138. DOI: 10.1136/gut.2007.143321.
  83. Emmerson E, May AJ, et al. SOX2 regulates acinar cell development in the salivary gland. Elife 2017 Jun 17;6, 10.7554/eLife.26620.
  84. Nanduri LS, Lombaert IM, et al. Salisphere derived c-Kit+ cell transplantation restores tissue homeostasis in irradiated salivary gland. Radiother Oncol 2013;108:458–463. DOI: 10.1016/j.radonc.2013.05.020.
  85. Augstein P, Loudovaris T, et al. Characterization of the Human Pancreas Side Population as a Potential Reservoir of Adult Stem Cells. Pancreas 2018;47:25–34.
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