Skip to main content
SpringerLink
Log in

Directed Cell Differentiation by Inductive Signals in Salivary Gland Regeneration: Lessons Learned from Pancreas and Liver Regeneration

  • Chapter
  • First Online:
Salivary Gland Development and Regeneration

  • 942 Accesses

Abstract

Xerostomia (dry mouth) is a deleterious condition that patients with radiation therapy for head and neck cancer or autoimmune Sjögren’s syndrome suffer from. Current remedies for this condition provide no substantial relief of xerostomia. As a result, new alternatives to these palliative remedies, such as artificial salivary glands, gene therapy, or cell-based interventions, are on the horizon. An urgent demand for acquisition of knowledge on stem cell regulation, which is critical for salivary gland regeneration, has allowed systematic and mechanistic research endeavor focusing on the identification of key regulators for cell lineage determination. This book chapter summarizes the key inductive signals, which include extrinsic factors secreted from the microenvironment and cell intrinsic factors that drive differentiation of the stem cells into the cells of the pancreas, liver, and salivary glands as they share the endodermal origin during development. The plethora of information available in pancreas and liver regeneration studies provides insight into key signals that govern vital processes during orchestrated stem cell differentiation for salivary epithelial cells. Some examples of transdifferentiation between differentiated cells of different organs and in vivo applications of inductive factors offer perspectives on future clinical applications with improved safety and efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjogren’s syndrome. Nat Rev Rheumatol. 2010;6:529–37.

    Article  PubMed  Google Scholar 

  2. Seiwert TY, Cohen EE, Haraf DJ, Stenson K, Blair EA, et al. A phase I trial of docetaxel based induction and concomitant chemotherapy in patients with locally advanced head and neck cancer. Cancer Invest. 2007;25:435–44.

    Article  PubMed  Google Scholar 

  3. Malouf JG, Aragon C, Henson BS, Eisbruch A, Ship JA. Influence of parotid-sparing radiotherapy on xerostomia in head and neck cancer patients. Cancer Detect Prev. 2003;27:305–10.

    Article  PubMed  Google Scholar 

  4. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol. 2003;66:253–62.

    Article  PubMed  Google Scholar 

  5. Dirix P, Nuyts S, Van den Bogaert W. Radiation-induced xerostomia in patients with head and neck cancer: a literature review. Cancer. 2006;107:2525–34.

    Article  PubMed  Google Scholar 

  6. Baum BJ. Prospects for re-engineering salivary glands. Adv Dent Res. 2000;14:84–8.

    Article  PubMed  Google Scholar 

  7. Feng J, van der Zwaag M, Stokman MA, van Os R, Coppes RP. Isolation and characterization of human salivary gland cells for stem cell transplantation to reduce radiation-induced hyposalivation. Radiother Oncol. 2009;92:466–71.

    Article  PubMed  Google Scholar 

  8. Lombaert IM, Knox SM, Hoffman MP. Salivary gland progenitor cell biology provides a rationale for therapeutic salivary gland regeneration. Oral Dis. 2011;17:445–9.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Pringle S, Van Os R, Coppes RP. Concise review: adult salivary gland stem cells and a potential therapy for xerostomia. Stem Cells. 2013;31:613–9.

    Article  PubMed  Google Scholar 

  10. Maria OM, Tran SD. Human mesenchymal stem cells cultured with salivary gland biopsies adopt an epithelial phenotype. Stem Cells Dev. 2011;20:959–67.

    Article  PubMed  Google Scholar 

  11. Sumita Y, Liu Y, Khalili S, Maria OM, Xia D, et al. Bone marrow-derived cells rescue salivary gland function in mice with head and neck irradiation. Int J Biochem Cell Biol. 2011;43:80–7.

    Article  PubMed  Google Scholar 

  12. Park YJ, Koh J, Gauna AE, Chen S, Cha S. Identification of regulatory factors for mesenchymal stem cell-derived salivary epithelial cells in a co-culture system. PLoS One. 2014;9:e112158.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Watt FM, Hogan BL. Out of Eden: stem cells and their niches. Science. 2000;287:1427–30.

    Article  PubMed  Google Scholar 

  14. Xu YX, Chen L, Wang R, Hou WK, Lin P, et al. Mesenchymal stem cell therapy for diabetes through paracrine mechanisms. Med Hypotheses. 2008;71:390–3.

    Article  PubMed  Google Scholar 

  15. Ichim TE, Alexandrescu DT, Solano F, Lara F, Campion Rde N, et al. Mesenchymal stem cells as anti-inflammatories: implications for treatment of Duchenne muscular dystrophy. Cell Immunol. 2010;260:75–82.

    Article  PubMed  Google Scholar 

  16. Sequeira SJ, Larsen M, DeVine T. Extracellular matrix and growth factors in salivary gland development. Front Oral Biol. 2010;14:48–77.

    Article  PubMed  Google Scholar 

  17. Gattazzo F, Urciuolo A, Bonaldo P. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta. 2014;1840:2506–19.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Maria OM, Zeitouni A, Gologan O, Tran SD. Matrigel improves functional properties of primary human salivary gland cells. Tissue Eng Part A. 2011;17:1229–38.

    Article  PubMed  Google Scholar 

  19. Leal-Egana A, Scheibel T. Silk-based materials for biomedical applications. Biotechnol Appl Biochem. 2010;55:155–67.

    Article  PubMed  Google Scholar 

  20. Kundu B, Kurland NE, Yadavalli VK, Kundu SC. Isolation and processing of silk proteins for biomedical applications. Int J Biol Macromol. 2014;70:70–7.

    Article  PubMed  Google Scholar 

  21. Anseth KS, Metters AT, Bryant SJ, Martens PJ, Elisseeff JH, et al. In situ forming degradable networks and their application in tissue engineering and drug delivery. J Control Release. 2002;78:199–209.

    Article  PubMed  Google Scholar 

  22. Nuttelman CR, Tripodi MC, Anseth KS. In vitro osteogenic differentiation of human mesenchymal stem cells photoencapsulated in PEG hydrogels. J Biomed Mater Res A. 2004;68:773–82.

    Article  PubMed  Google Scholar 

  23. Benoit DS, Durney AR, Anseth KS. The effect of heparin-functionalized PEG hydrogels on three-dimensional human mesenchymal stem cell osteogenic differentiation. Biomaterials. 2007;28:66–77.

    Article  PubMed  Google Scholar 

  24. Weber LM, He J, Bradley B, Haskins K, Anseth KS. PEG-based hydrogels as an in vitro encapsulation platform for testing controlled beta-cell microenvironments. Acta Biomater. 2006;2:1–8.

    Article  PubMed  Google Scholar 

  25. Lin CC, Raza A, Shih H. PEG hydrogels formed by thiol-ene photo-click chemistry and their effect on the formation and recovery of insulin-secreting cell spheroids. Biomaterials. 2011;32:9685–95.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mahoney MJ, Anseth KS. Three-dimensional growth and function of neural tissue in degradable polyethylene glycol hydrogels. Biomaterials. 2006;27:2265–74.

    Article  PubMed  Google Scholar 

  27. Benoit DS, Schwartz MP, Durney AR, Anseth KS. Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat Mater. 2008;7:816–23.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Weber LM, Anseth KS. Hydrogel encapsulation environments functionalized with extracellular matrix interactions increase islet insulin secretion. Matrix Biol. 2008;27:667–73.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lin CC, Anseth KS. Cell-cell communication mimicry with poly(ethylene glycol) hydrogels for enhancing beta-cell function. Proc Natl Acad Sci U S A. 2011;108:6380–5.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Pradhan S, Liu C, Zhang C, Jia X, Farach-Carson MC, et al. Lumen formation in three-dimensional cultures of salivary acinar cells. Otolaryngol Head Neck Surg. 2010;142:191–5.

    Article  PubMed  Google Scholar 

  31. Walker JL, Menko AS, Khalil S, Rebustini I, Hoffman MP, et al. Diverse roles of E-cadherin in the morphogenesis of the submandibular gland: insights into the formation of acinar and ductal structures. Dev Dyn. 2008;237:3128–41.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Davis MA, Reynolds AB. Blocked acinar development, E-cadherin reduction, and intraepithelial neoplasia upon ablation of p120-catenin in the mouse salivary gland. Dev Cell. 2006;10:21–31.

    Article  PubMed  Google Scholar 

  33. Okumura K, Shinohara M, Endo F. Capability of tissue stem cells to organize into salivary rudiments. Stem Cells Int. 2012;2012:502136.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shubin AD, Felong TJ, Graunke D, Ovitt CE, Benoit DS. Development of poly(ethylene glycol) hydrogels for salivary gland tissue engineering applications. Tissue Eng Part A. 2015;21:1733–51.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sander, M., Seymour, P., Kopp, J., Shih, B., Patel, N. & Lim, C. Molecular cues regulating segregation of pancreatic, hepatic and intestinal lineages. The FASEB Journal 2011;25, 303.3.

    Google Scholar 

  36. Zaret KS. Regulatory phases of early liver development: paradigms of organogenesis. Nat Rev Genet. 2002;3:499–512.

    Article  PubMed  Google Scholar 

  37. Wandzioch E, Zaret KS. Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science. 2009;324:1707–10.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bonal C, Herrera PL. Genes controlling pancreas ontogeny. Int J Dev Biol. 2008;52:823–35.

    Article  PubMed  Google Scholar 

  39. Gittes GK. Developmental biology of the pancreas: a comprehensive review. Dev Biol. 2009;326:4–35.

    Article  PubMed  Google Scholar 

  40. Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev. 2001;15:111–27.

    Article  PubMed  Google Scholar 

  41. Mfopou JK, Chen B, Sui LN, Sermon K, Bouwens L. Recent advances and prospects in the differentiation of pancreatic cells from human embryonic stem cells. Diabetes. 2010;59:2094–101.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Patel VN, Rebustini IT, Hoffman MP. Salivary gland branching morphogenesis. Differentiation. 2006;74:349–64.

    Article  PubMed  Google Scholar 

  43. Dalvi MP, Umrani MR, Joglekar MV, Hardikar AA. Human pancreatic islet progenitor cells demonstrate phenotypic plasticity in vitro. J Biosci. 2009;34:523–8.

    Article  PubMed  Google Scholar 

  44. Hardikar AA, Marcus-Samuels B, Geras-Raaka E, Raaka BM, Gershengorn MC. Human pancreatic precursor cells secrete FGF2 to stimulate clustering into hormone-expressing islet-like cell aggregates. Proc Natl Acad Sci U S A. 2003;100:7117–22.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Si-Tayeb K, Noto FK, Nagaoka M, Li JX, Battle MA, et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells (vol 51, pg 297, 2010). Hepatology. 2010;51:1094.

    Article  Google Scholar 

  46. Cras-Meneur C, Elghazi L, Czernichow P, Scharfmann R. Epidermal growth factor increases undifferentiated pancreatic embryonic cells in vitro – a balance between proliferation and differentiation. Diabetes. 2001;50:1571–9.

    Article  PubMed  Google Scholar 

  47. Kitade M, Factor VM, Andersen JB, Tomokuni A, Kaji K, et al. Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev. 2013;27:1706–17.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kashimata M, Sayeed S, Ka A, Onetti-Muda A, Sakagami H, et al. The ERK-1/2 signaling pathway is involved in the stimulation of branching morphogenesis of fetal mouse submandibular glands by EGF. Dev Biol. 2000;220:183–96.

    Article  PubMed  Google Scholar 

  49. Demeterco C, Beattie GM, Dib SA, Lopez AD, Hayek A. A role for activin A and betacellulin in human fetal pancreatic cell differentiation and growth. J Clin Endocrinol Metab. 2000;85:3892–7.

    PubMed  Google Scholar 

  50. Chen LB, Jiang XB, Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells. World J Gastroenterol. 2004;10:3016–20.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Segev H, Fishman B, Ziskind A, Shulman M, Itskovitz-Eldor J. Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells. 2004;22:265–74.

    Article  PubMed  Google Scholar 

  52. Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, et al. In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes. 2004;53:1721–32.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sun Y, Chen L, Hou XG, Hou WK, Dong JJ, et al. Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro. Chin Med J (Engl). 2007;120:771–6.

    Google Scholar 

  54. Sun B, Roh KH, Lee SR, Lee YS, Kang KS. Induction of human umbilical cord blood-derived stem cells with embryonic stem cell phenotypes into insulin producing islet-like structure. Biochem Biophys Res Commun. 2007;354:919–23.

    Article  PubMed  Google Scholar 

  55. Wu XH, Liu CP, Xu KF, Mao XD, Zhu J, et al. Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells. World J Gastroenterol. 2007;13:3342–9.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Chao KC, Chao KF, Fu YS, Liu SH. Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One. 2008;3:e1451.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Gabr MM, Sobh MM, Zakaria MM, Refaie AF, Ghoneim MA. Transplantation of insulin-producing clusters derived from adult bone marrow stem cells to treat diabetes in rats. Exp Clin Transplant. 2008;6:236–43.

    PubMed  Google Scholar 

  58. Gao F, Wu DQ, Hu YH, Jin GX. Extracellular matrix gel is necessary for in vitro cultivation of insulin producing cells from human umbilical cord blood derived mesenchymal stem cells. Chin Med J (Engl). 2008;121:811–8.

    Google Scholar 

  59. Otonkoski T, Beattie GM, Mally MI, Ricordi C, Hayek A. Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. J Clin Invest. 1993;92:1459–66.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Gao F, Wu DQ, Hu YH, Jin GX, Li GD, et al. In vitro cultivation of islet-like cell clusters from human umbilical cord blood-derived mesenchymal stem cells. Transl Res. 2008;151:293–302.

    Article  PubMed  Google Scholar 

  61. Aguayo-Mazzucato C, Koh A, El Khattabi I, Li WC, Toschi E, et al. Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells. Diabetologia. 2011;54:583–93.

    Article  PubMed  Google Scholar 

  62. Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, et al. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun. 2006;341:1135–40.

    Article  PubMed  Google Scholar 

  63. Mashima H, Shibata H, Mine T, Kojima I. Formation of insulin-producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. Endocrinology. 1996;137:3969–76.

    PubMed  Google Scholar 

  64. Otonkoski T, Cirulli V, Beattie GM, Mally MI, Soto G, et al. A role for hepatocyte growth factor/scatter factor in fetal mesenchyme-induced pancreatic beta-cell growth. Endocrinology. 1996;137:3131–9.

    PubMed  Google Scholar 

  65. Onitsuka I, Tanaka M, Miyajima A. Characterization and functional analyses of hepatic mesothelial cells in mouse liver development. Gastroenterology. 2010;138:1525–U1395.

    Article  PubMed  Google Scholar 

  66. Ishikawa T, Factor VM, Marquardt JU, Raggi C, Seo D, et al. Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice. Hepatology. 2012;55:1215–26.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Wang TC, Bonnerweir S, Oates PS, Chulak M, Simon B, et al. Pancreatic gastrin stimulates islet differentiation of transforming growth-factor alpha-induced ductular precursor cells. J Clin Investig. 1993;92:1349–56.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Wang RN, Rehfeld JF, Nielsen FC, Kloppel G. Expression of gastrin and transforming growth factor-alpha during duct to islet cell differentiation in the pancreas of duct-ligated adult rats. Diabetologia. 1997;40:887–93.

    Article  PubMed  Google Scholar 

  69. Halban PA, Powers SL, George KL, Bonnerweir S. Spontaneous reassociation of dispersed adult-rat pancreatic-islet cells into aggregates with 3-dimensional architecture typical of native islets. Diabetes. 1987;36:783–90.

    Article  PubMed  Google Scholar 

  70. Kamiya A, Kinoshita T, Ito Y, Matsui T, Morikawa Y, et al. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J. 1999;18:2127–36.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kamiya A, Kojima N, Kinoshita T, Sakai Y, Miyaijma A. Maturation of fetal hepatocytes in vitro by extracellular matrices and oncostatin M: induction of tryptophan oxygenase. Hepatology. 2002;35:1351–9.

    Article  PubMed  Google Scholar 

  72. Matsui T, Kinoshita T, Hirano T, Yokota T, Miyajima A. STAT3 down-regulates the expression of cyclin D during liver development. J Biol Chem. 2002;277:36167–73.

    Article  PubMed  Google Scholar 

  73. Banas A, Yamamoto Y, Teratani T, Ochiya T. Stem cell plasticity: Learning from hepatogenic differentiation strategies. Dev Dyn. 2007;236:3228–41.

    Article  PubMed  Google Scholar 

  74. Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004;103:1669–75.

    Article  PubMed  Google Scholar 

  75. Arany S, Catalan MA, Roztocil E, Ovitt CE. Ascl3 knockout and cell ablation models reveal complexity of salivary gland maintenance and regeneration. Dev Biol. 2011;353:186–93.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree GR. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha-1-antitrypsin promoters. Science. 1987;238:688–92.

    Article  PubMed  Google Scholar 

  77. Cereghini S, Blumenfeld M, Yaniv M. A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma-cells. Genes Dev. 1988;2:957–74.

    Article  PubMed  Google Scholar 

  78. Ishiyama T, Kano J, Minami Y, Iijima T, Morishita Y, et al. Expression of HNFs and C/EBP alpha is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytes. Cancer Sci. 2003;94:757–63.

    Article  PubMed  Google Scholar 

  79. Gao N, LeLay J, Vatamaniuk MZ, Rieck S, Friedman JR, et al. Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev. 2008;22:3435–48.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Xu CH, Lu XW, Chen EZ, He ZY, Uyunbilig B, et al. Genome-wide roles of Foxa2 in directing liver specification. J Mol Cell Biol. 2012;4:420–2.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gao N, White P, Doliba N, Golson ML, Matschinsky FM, et al. Foxa2 controls vesicle docking and insulin secretion in mature beta cells. Cell Metab. 2007;6:267–79.

    Article  PubMed  Google Scholar 

  82. Carrasco M, Delgado I, Soria B, Martin F, Rojas A. GATA4 and GATA6 control mouse pancreas organogenesis. J Clin Invest. 2012;122:3504–15.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Haumaitre C, Barbacci E, Jenny M, Ott MO, Gradwohl G, et al. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc Natl Acad Sci U S A. 2005;102:1490–5.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Watt AJ, Garrison WD, Duncan SA. HNF4: a central regulator of hepatocyte differentiation and function. Hepatology. 2003;37:1249–53.

    Article  PubMed  Google Scholar 

  85. Pierreux CE, Vanhorenbeeck V, Jacquemin P, Lemaigre FP, Rousseau GG. The transcription factor hepatocyte nuclear factor-6/Onecut-1 controls the expression of its paralog Onecut-3 in developing mouse endoderm. J Biol Chem. 2004;279:51298–304.

    Article  PubMed  Google Scholar 

  86. Du A, Hunter CS, Murray J, Noble D, Cai CL, et al. Islet-1 is required for the maturation, proliferation, and survival of the endocrine pancreas. Diabetes. 2009;58:2059–69.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Pin CL, Rukstalis JM, Johnson C, Konieczny SF. The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J Cell Biochem. 2001;155:519–30.

    Google Scholar 

  88. Imai Y, Patel HR, Hawkins EJ, Doliba NM, Matschinsky FM, et al. Insulin secretion is increased in pancreatic islets of neuropeptide Y-deficient mice. Endocrinology. 2007;148:5716–23.

    Article  PubMed  Google Scholar 

  89. Gu C, Stein GH, Pan N, Goebbels S, Hornberg H, et al. Pancreatic beta cells require NeuroD to achieve and maintain functional maturity. Cell Metab. 2010;11:298–310.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Magenheim J, Klein AM, Stanger BZ, Ashery-Padan R, Sosa-Pineda B, et al. Ngn3(+) endocrine progenitor cells control the fate and morphogenesis of pancreatic ductal epithelium. Dev Biol. 2011;359:26–36.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Papizan JB, Singer RA, Tschen SI, Dhawan S, Friel JM, et al. Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming. Genes Dev. 2011;25:2291–305.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Taylor BL, Liu FF, Sander M. Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep. 2013;4:1262–75.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, et al. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19:146–54.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Bonnefond A, Vaillant E, Philippe J, Skrobek B, Lobbens S, et al. Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family. Diabetes Metab. 2013;39:276–80.

    Article  PubMed  Google Scholar 

  95. Hart AW, Mella S, Mendrychowski J, van Heyningen V, Kleinjan DA. The developmental regulator Pax6 is essential for maintenance of islet cell function in the adult mouse pancreas. PLoS One. 2013;8:e54173.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Jennings RE, Berry AA, Kirkwood-Wilson R, Roberts NA, Hearn T, et al. Development of the human pancreas from foregut to endocrine commitment. Diabetes. 2013;62:3514–22.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development. 2002;129:2447–57.

    PubMed  Google Scholar 

  98. Brissova M, Blaha M, Spear C, Nicholson W, Radhika A, et al. Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis. Am J Physiol Endocrinol Metab. 2005;288:E707–14.

    Article  PubMed  Google Scholar 

  99. Yoshitomi H, Zaret KS. Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development. 2004;131:807–17.

    Article  PubMed  Google Scholar 

  100. Weedon MN, Cebola I, Patch AM, Flanagan SE, De Franco E, et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet. 2014;46:61–4.

    Article  PubMed  Google Scholar 

  101. Kawaguchi Y. Sox9 and programming of liver and pancreatic progenitors. J Clin Invest. 2013;123:1881–6.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Mead TJ, Wang Q, Bhattaram P, Dy P, Afelik S, et al. A far-upstream (−70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration. Nucleic Acids Res. 2013;41:4459–69.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Kanai-Azuma M, Kanai Y, Gad JM, Tajima Y, Taya C, et al. Depletion of definitive gut endoderm in Sox17-null mutant mice. Development. 2002;129:2367–79.

    PubMed  Google Scholar 

  104. Tran SD, Liu YN, Xia DS, Maria OM, Khalili S, et al. Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation. PLoS One. 2013;8:e61632.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.

    Article  PubMed  Google Scholar 

  106. Fang D, Hu S, Liu Y, Quan VH, Seuntjens J, et al. Identification of the active components in Bone Marrow Soup: a mitigator against irradiation-injury to salivary glands. Sci Rep. 2015;5:16017.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Entesarian M, Dahlqvist J, Shashi V, Stanley CS, Falahat B, et al. FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG). Eur J Hum Genet. 2007;15:379–82.

    Article  PubMed  Google Scholar 

  108. Scheckenbach K, Balz V, Wagenmann M, Hoffmann TK. An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome. BMC Med Genet. 2008;9:114.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Lombaert IMA, Brunsting JF, Wierenga PK, Kampinga HH, De Haan G, et al. Keratinocyte growth factor prevents radiation damage to salivary glands by expansion of the stem/progenitor pool. Stem Cells. 2008;26:2595–601.

    Article  PubMed  Google Scholar 

  110. Panman L, Andersson E, Alekseenko Z, Hedlund E, Kee N, et al. Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells. Cell Stem Cell. 2011;8:663–75.

    Article  PubMed  Google Scholar 

  111. Jones S. An overview of the basic helix-loop-helix proteins. Genome Biol. 2004;5:226.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Fairman R, Beran-Steed RK, Anthony-Cahill SJ, Lear JD, Stafford 3rd WF, et al. Multiple oligomeric states regulate the DNA binding of helix-loop-helix peptides. Proc Natl Acad Sci U S A. 1993;90:10429–33.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Shih HP, Seymour PA, Patel NA, Xie R, Wang A, et al. A gene regulatory network cooperatively controlled by Pdx1 and Sox9 governs lineage allocation of foregut progenitor cells. Cell Rep. 2015;13:326–36.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Kawakami M, Ishikawa H, Tachibana T, Tanaka A, Mataga I. Functional transplantation of salivary gland cells differentiated from mouse early ES cells in vitro. Hum Cell. 2013;26:80–90.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455:627–U630.

    Article  PubMed  Google Scholar 

  116. Lima MJ, Muir KR, Docherty HM, Drummond R, McGowan NWA, et al. Suppression of epithelial-to-mesenchymal transitioning enhances ex vivo reprogramming of human exocrine pancreatic tissue toward functional insulin-producing beta-like cells. Diabetes. 2013;62:2821–33.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Li L, Yi ZH, Seno M, Kojima I. Activin A and betacellulin – effect on regeneration of pancreatic beta-cells in neonatal streptozotocin-treated rats. Diabetes. 2004;53:608–15.

    Article  PubMed  Google Scholar 

  118. Huang PY, He ZY, Ji SY, Sun HW, Xiang D, et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature. 2011;475:386–U142.

    Article  PubMed  Google Scholar 

  119. Yu B, He ZY, You P, Han QW, Xiang D, et al. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell. 2013;13:328–40.

    Article  PubMed  Google Scholar 

  120. Ahlgren U, Pfaff SL, Jessell TM, Edlund T, Edlund H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature. 1997;385:257–60.

    Article  PubMed  Google Scholar 

  121. Edlund H. Pancreatic organogenesis – developmental mechanisms and implications for therapy. Nat Rev Genet. 2002;3:524–32.

    Article  PubMed  Google Scholar 

  122. Matsuoka TA, Kaneto H, Miyatsuka T, Yamamoto T, Yamamoto K, et al. Regulation of MafA expression in pancreatic beta-cells in db/db mice with diabetes. Diabetes. 2010;59:1709–20.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Harmon JS, Bogdani M, Parazzoli SD, Mak SS, Oseid EA, et al. Beta-Cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice. Endocrinology. 2009;150:4855–62.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Butler AE, Robertson RP, Hernandez R, Matveyenko AV, Gurlo T, et al. Beta cell nuclear musculoaponeurotic fibrosarcoma oncogene family A (MafA) is deficient in type 2 diabetes. Diabetologia. 2012;55:2985–8.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Guo S, Dai C, Guo M, Taylor B, Harmon JS, et al. Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Invest. 2013;123:3305–16.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012;150:1223–34.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Ghaye AP, Bergemann D, Tarifeno-Saldivia E, Flasse LC, Von Berg V, et al. Progenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration. BMC Biol. 2015;13:70.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR. Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in beta-cell gene expression and progression to diabetes. Diabetes. 2013;62:1557–68.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Li H, Arber S, Jessell TM, Edlund H. Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet. 1999;23:67–70.

    PubMed  Google Scholar 

  130. Conrad E, Stein R, Hunter CS. Revealing transcription factors during human pancreatic beta cell development. Trends Endocrinol Metab. 2014;25:407–14.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Hamasaki A, Yamada Y, Kurose T, Ban N, Nagashima K, et al. Adult pancreatic islets require differential pax6 gene dosage. Biochem Biophys Res Commun. 2007;353:40–6.

    Article  PubMed  Google Scholar 

  132. Wen JH, Chen YY, Song SJ, Ding J, Gao Y, et al. Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3). Diabetologia. 2009;52:504–13.

    Article  PubMed  Google Scholar 

  133. Ding J, Gao Y, Zhao J, Yan H, Guo SY, et al. Pax6 haploinsufficiency causes abnormal metabolic homeostasis by down-regulating glucagon-like peptide 1 in mice. Endocrinology. 2009;150:2136–44.

    Article  PubMed  Google Scholar 

  134. Habener JF, Kemp DM, Thomas MK. Minireview: transcriptional regulation in pancreatic development. Endocrinology. 2005;146:1025–34.

    Article  PubMed  Google Scholar 

  135. Fujimoto K, Polonsky KS. Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes Obes Metab. 2009;11:30–7.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Spence JR, Lange AW, Lin SCJ, Kaestner KH, Lowy AM, et al. Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev Cell. 2009;17:62–74.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Kamiya A, Inoue Y, Gonzalez FJ. Role of the hepatocyte nuclear factor 4 alpha in control of the pregnane X receptor during fetal liver development. Hepatology. 2003;37:1375–84.

    Article  PubMed  Google Scholar 

  138. Li JX, Ning G, Duncan SA. Mammalian hepatocyte differentiation requires the transcription factor HNF-4 alpha. Genes Dev. 2000;14:464–74.

    PubMed  PubMed Central  Google Scholar 

  139. Jin JL, Iakova P, Jiang YJ, Lewis K, Sullivan E, et al. Transcriptional and translational regulation of C/EBP beta-HDAC1 protein complexes controls different levels of p53, SIRT1, and PGC1 alpha proteins at the early and late stages of liver cancer. J Biol Chem. 2013;288:14451–62.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Schrem H, Klempnauer J, Borlak J. Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. Pharmacol Rev. 2004;56:291–330.

    Article  PubMed  Google Scholar 

  141. Flodby P, Barlow C, Kylefjord H, Ahrlund-Richter L, Xanthopoulos KG. Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein alpha. J Biol Chem. 1996;271:24753–60.

    Article  PubMed  Google Scholar 

  142. Nakamura T, Ueno T, Sakamoto M, Sakata R, Torimura T, et al. Suppression of transforming growth factor-beta results in upregulation of transcription of regeneration factors after chronic liver injury. J Hepatol. 2004;41:974–82.

    Article  PubMed  Google Scholar 

  143. Fausto N. Liver regeneration. J Hepatol. 2000;32:19–31.

    Article  PubMed  Google Scholar 

  144. Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA. Liver regeneration. J Am Coll Surg. 2003;197:634–59.

    Article  PubMed  Google Scholar 

  145. Crissey MAS, Leu JI, De Angelis RA, Greenbaum LE, Scearce LM, et al. Liver-specific and proliferation-induced deoxyribonuclease I hypersensitive sites in the mouse insulin-like growth factor binding protein-1 gene. Hepatology. 1999;30:1187–97.

    Article  PubMed  Google Scholar 

  146. Tomizawa M, Garfield S, Xanthopoulos KG. Hepatocytes deficient in CCAAT enhancer binding protein alpha (C/EBP alpha) exhibit both hepatocyte and biliary epithelial cell character. Hepatology. 1998;28:294a.

    Google Scholar 

  147. Yamasaki H, Sada A, Iwata T, Niwa T, Tomizawa M, et al. Suppression of C/EBP alpha expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1b expression. Development. 2006;133:4233–43.

    Article  PubMed  Google Scholar 

  148. Antoniou A, Raynaud P, Cordi S, Zong YW, Tronche F, et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology. 2009;136:2325–33.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Bullard T, Koek L, Roztocil E, Kingsley PD, Mirels L, et al. Ascl3 expression marks a progenitor population of both acinar and ductal cells in mouse salivary glands. Dev Biol. 2008;320:72–8.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yoshida S, Ohbo K, Takakura A, Takebayashi H, Okada T, et al. Sgn1, a basic helix-loop-helix transcription factor delineates the salivary gland duct cell lineage in mice. Dev Biol. 2001;240:517–30.

    Article  PubMed  Google Scholar 

  151. Aure MH, Konieczny SF, Ovitt CE. Salivary gland homeostasis is maintained through acinar cell self-duplication. Dev Cell. 2015;33:231–7.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Gagliardi A, Mullin NP, Tan ZY, Colby D, Kousa AI, et al. A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal. EMBO J. 2013;32:2231–47.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Knox SM, Lombaert IM, Reed X, Vitale-Cross L, Gutkind JS, et al. Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science. 2010;329:1645–7.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Pereira L, Yi F, Merrill BJ. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol Cell Biol. 2006;26:7479–91.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Wray J, Kalkan T, Gomez-Lopez S, Eckardt D, Cook A, et al. Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nat Cell Biol. 2011;13:838–45.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Kelly KF, Ng DY, Jayakumaran G, Wood GA, Koide H, et al. Beta-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell Stem Cell. 2011;8:214–27.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Yi F, Pereira L, Hoffman JA, Shy BR, Yuen CM, et al. Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol. 2011;13:762–U383.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Atlasi Y, Noori R, Gaspar C, Franken P, Sacchetti A, et al. Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation. PLoS Genet. 2013;9:e1003424.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Wu CI, Hoffman JA, Shy BR, Ford EM, Fuchs E, et al. Function of Wnt/beta-catenin in counteracting Tcf3 repression through the Tcf3-beta-catenin interaction. Development. 2012;139:2118–29.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Marmorstein LY, Kinev AV, Chan GKT, Bochar DA, Beniya H, et al. A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression. Cell. 2001;104:247–57.

    Article  PubMed  Google Scholar 

  161. Lin JW, Biankin AV, Horb ME, Ghosh B, Prasad NB, et al. Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Dev Biol. 2004;274:491–503.

    Article  PubMed  Google Scholar 

  162. Cano DA, Soria B, Martin F, Rojas A. Transcriptional control of mammalian pancreas organogenesis. Cell Mol Life Sci. 2014;71:2383–402.

    Article  PubMed  Google Scholar 

  163. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424:443–7.

    Article  PubMed  Google Scholar 

  164. Watt AJ, Zhao R, Li JX, Duncan SA. Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev Biol. 2007;7:37.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Lee CS, Sund NJ, Vatamaniuk MZ, Matschinsky FM, Stoffers DA, et al. Foxa2 controls Pdx1 gene expression in pancreatic beta-cells in vivo. Diabetes. 2002;51:2546–51.

    Article  PubMed  Google Scholar 

  166. Lee CS, Sund NJ, Behr R, Herrera PL, Kaestner KH. Foxa2 is required for the differentiation of pancreatic alpha-cells. Dev Biol. 2005;278:484–95.

    Article  PubMed  Google Scholar 

  167. Zaret KS, Carroll JS. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 2011;25:2227–41.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Le Lay J, Kaestner KH. The fox genes in the liver: from organogenesis to functional integration. Physiol Rev. 2010;90:1–22.

    Article  PubMed  Google Scholar 

  169. Jeon J, Correa-Medina M, Ricordi C, Edlund H, Diez JA. Endocrine cell clustering during human pancreas development. J Histochem Cytochem. 2009;57:811–24.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Rubio-Cabezas O, Jensen JN, Hodgson MI, Codner E, Ellard S, et al. Permanent neonatal diabetes and enteric anendocrinosis associated with biallelic mutations in NEUROG3. Diabetes. 2011;60:1349–53.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Gradwohl G, Dierich A, LeMeur M, Guillemot F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A. 2000;97:1607–11.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Johnson CL, Kowalik AS, Rajakumar N, Pin CL. Mist1 is necessary for the establishment of granule organization in serous exocrine cells of the gastrointestinal tract. Mech Dev. 2004;121:261–72.

    Article  PubMed  Google Scholar 

  173. Pin CL, Bonvissuto AC, Konieczny SF. Mist1 expression is a common link among serous exocrine cells exhibiting regulated exocytosis. Anat Rec. 2000;259:157–67.

    Article  PubMed  Google Scholar 

  174. Direnzo D, Hess DA, Damsz B, Hallett JE, Marshall B, et al. Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells. Gastroenterology. 2012;143:469–80.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Rukstalis JM, Kowalik A, Zhu LQ, Lidington D, Pin CL, et al. Exocrine specific expression of Connexin32 is dependent on the basic helix-loop-helix transcription factor Mist1. J Cell Sci. 2003;116:3315–25.

    Article  PubMed  Google Scholar 

  176. Pan FC, Wright C. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn. 2011;240:530–65.

    Article  PubMed  Google Scholar 

  177. McDonald E, Li JM, Krishnamurthy M, Fellows GF, Goodyer CG, et al. SOX9 regulates endocrine cell differentiation during human fetal pancreas development. Int J Biochem Cell Biol. 2012;44:72–83.

    Article  PubMed  Google Scholar 

  178. Selman K, Kafatos FC. Transdifferentiation in the labial gland of silk moths: is DNA required for cellular metamorphosis? Cell Differ. 1974;3:81–94.

    Article  PubMed  Google Scholar 

  179. Eguchi G, Okada TS. Differentiation of lens tissue from the progeny of chick retinal pigment cells cultured in vitro: a demonstration of a switch of cell types in clonal cell culture. Proc Natl Acad Sci U S A. 1973;70:1495–9.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Araki M, Okada TS. Differentiation of lens and pigment cells in cultures of neural retinal cells of early chick embryos. Dev Biol. 1977;60:278–86.

    Article  PubMed  Google Scholar 

  181. Bronnerfraser M. Transdifferentiation – flexibility in cell-differentiation – Okada, Ts. Science. 1992;256:1054–5.

    Article  Google Scholar 

  182. Eberhard D, Tosh D. Transdifferentiation and metaplasia as a paradigm for understanding development and disease. Cell Mol Life Sci. 2008;65:33–40.

    Article  PubMed  Google Scholar 

  183. Gruh IMU. Transdifferentiation of stem cells: a critical view. In: Martin U, editor. Engineering of stem cells. Heidelberg: Springer; 2009. p. 73–106.

    Chapter  Google Scholar 

  184. Burke ZD, Tosh D. Therapeutic potential of transdifferentiated cells. Clin Sci (Lond). 2005;108:309–21.

    Article  Google Scholar 

  185. Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, et al. Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci U S A. 2013;110:7038–43.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Merrell AJ, Stanger BZ. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol. 2016;17:413–145.

    Article  PubMed  Google Scholar 

  187. Burke ZD, Thowfeequ S, Peran M, Tosh D. Stem cells in the adult pancreas and liver. Biochem J. 2007;404:169–78.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Kume S. Stem-cell-based approaches for regenerative medicine. Dev Growth Differ. 2005;47:393–402.

    Article  PubMed  Google Scholar 

  189. Dabeva MD, Hurston E, Shafritz DA. Transcription factor and liver-specific mRNA expression in facultative epithelial progenitor cells of liver and pancreas. Am J Pathol. 1995;147:1633–48.

    PubMed  PubMed Central  Google Scholar 

  190. McLin VA, Zorn AM. Organogenesis: making pancreas from liver. Curr Biol. 2003;13:R96–8.

    Article  PubMed  Google Scholar 

  191. Horb ME, Shen CN, Tosh D, Slack JMW. Experimental conversion of liver to pancreas. Curr Biol. 2003;13:105–15.

    Article  PubMed  Google Scholar 

  192. Kojima H, Nakamura T, Fujita Y, Kishi A, Fujimiya M, et al. Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin. Diabetes. 2002;51:1398–408.

    Article  PubMed  Google Scholar 

  193. von Mach MA, Hengstler JG, Brulport M, Eberhardt M, Schormann W, et al. In vitro cultured islet-derived progenitor cells of human origin express human albumin in severe combined immunodeficiency mouse liver in vivo. Stem Cells. 2004;22:1134–41.

    Article  Google Scholar 

  194. Lardon J, De Breuck S, Rooman I, Van Lommel L, Kruhoffer M, et al. Plasticity in the adult rat pancreas: Transdifferentiation of exocrine to hepatocyte-like cells in primary culture. Hepatology. 2004;39:1499–507.

    Article  PubMed  Google Scholar 

  195. Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, et al. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet. 2002;32:128–34.

    Article  PubMed  Google Scholar 

  196. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med. 2000;6:568–72.

    Article  PubMed  Google Scholar 

  197. Yi F, Liu GH, Izpisua Belmonte JC. Rejuvenating liver and pancreas through cell transdifferentiation. Cell Res. 2012;22:616–9.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Kaneto H, Nakatani Y, Miyatsuka T, Matsuoka T, Matsuhisa M, et al. PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes. 2005;54:1009–22.

    Article  PubMed  Google Scholar 

  199. Hisatomi Y, Okumura K, Nakamura K, Matsumoto S, Satoh A, et al. Flow cytometric isolation of endodermal progenitors from mouse salivary gland differentiate into hepatic and pancreatic lineages. Hepatology. 2004;39:667–75.

    Article  PubMed  Google Scholar 

  200. Rothova M, Thompson H, Lickert H, Tucker AS. Lineage tracing of the endoderm during oral development. Dev Dyn. 2012;241:1183–91.

    Article  PubMed  Google Scholar 

  201. Okumura K, Nakamura K, Hisatomi Y, Nagano K, Tanaka Y, et al. Salivary gland progenitor cells induced by duct ligation differentiate into hepatic and pancreatic lineages. Hepatology. 2003;38:104–13.

    Article  PubMed  Google Scholar 

  202. Denny PC, Denny PA. Dynamics of parenchymal cell division, differentiation, and apoptosis in the young adult female mouse submandibular gland. Anat Rec. 1999;254:408–17.

    Article  PubMed  Google Scholar 

  203. Konings AW, Coppes RP, Vissink A. On the mechanism of salivary gland radiosensitivity. Int J Radiat Oncol Biol Phys. 2005;62:1187–94.

    Article  PubMed  Google Scholar 

  204. Patel VN, Hoffman MP. Salivary gland development: a template for regeneration. Semin Cell Dev Biol. 2014;25:52–60.

    Article  PubMed  Google Scholar 

  205. Nanduri LS, Maimets M, Pringle SA, van der Zwaag M, van Os RP, et al. Regeneration of irradiated salivary glands with stem cell marker expressing cells. Radiother Oncol. 2011;99:367–72.

    Article  PubMed  Google Scholar 

  206. Rock JR, Onaitis MW, Rawlins EL, Lu Y, Clark CP, et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci U S A. 2009;106:12771–5.

    Article  PubMed  PubMed Central  Google Scholar 

  207. Arnold K, Sarkar A, Yram MA, Polo JM, Bronson R, et al. Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell. 2011;9:317–29.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Nelson J, Manzella K, Baker OJ. Current cell models for bioengineering a salivary gland: a mini-review of emerging technologies. Oral Dis. 2013;19:236–44.

    Article  PubMed  PubMed Central  Google Scholar 

  209. Maimets M, Rocchi C, Bron R, Pringle S, Kuipers J, et al. Long-term in vitro expansion of salivary gland stem cells driven by Wnt signals. Stem Cells Rep. 2016;6:150–62.

    Article  Google Scholar 

  210. Yaniv A, Neumann Y, David R, Stiubea-Cohen R, Orbach Y, et al. Establishment of immortal multipotent rat salivary progenitor cell line toward salivary gland regeneration. Tissue Eng Part C Methods. 2011;17:69–78.

    Article  PubMed  Google Scholar 

  211. Sutton, M.T. & Bonfield, T.L. Stem cells: innovations in clinical applications. Stem Cells Int 2014, 516278 (2014).

    Google Scholar 

  212. Shamoon H, Duffy H, Fleischer N, Engel S, Saenger P, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes-mellitus. N Engl J Med. 1993;329:977–86.

    Article  Google Scholar 

  213. Bouwens L, Houbracken I, Mfopou JK. The use of stem cells for pancreatic regeneration in diabetes mellitus. Nat Rev Endocrinol. 2013;9:598–606.

    Article  PubMed  Google Scholar 

  214. Gennero L, Roos MA, Sperber K, Denysenko T, Bernabei P, et al. Pluripotent plasticity of stem cells and liver repopulation. Cell Biochem Funct. 2010;28:178–89.

    Article  PubMed  Google Scholar 

  215. Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell. 2014;14:561–74.

    Article  PubMed  Google Scholar 

  216. Schwartz RE, Reyes M, Koodie L, Jiang YH, Blackstad M, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Investig. 2002;109:1291–302.

    Article  PubMed  PubMed Central  Google Scholar 

  217. Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, et al. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells (Retracted article. See vol. 113, pg. 2370, 2009). Blood. 2001;98:2615–25.

    Article  PubMed  Google Scholar 

  218. Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica. 2006;91:1017–26.

    PubMed  Google Scholar 

  219. Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46:219–28.

    Article  PubMed  Google Scholar 

  220. Talens-Visconti R, Bonora A, Jover R, Mirabet V, Carbonell F, et al. Human mesenchymal stem cells from adipose tissue: Differentiation into hepatic lineage. Toxicol In Vitro. 2007;21:324–9.

    Article  PubMed  Google Scholar 

  221. Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, et al. Plasticity of human adipose lineage cells toward endothelial cells – physiological and therapeutic perspectives. Circulation. 2004;109:656–63.

    Article  PubMed  Google Scholar 

  222. Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun. 2005;328:258–64.

    Article  PubMed  Google Scholar 

  223. Lange C, Bassler P, Lioznov MV, Bruns H, Kluth D, et al. Liver-specific gene expression in mesenchymal stem cells is induced by liver cells. World J Gastroenterol. 2005;11:4497–504.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Rai RM, Yang SQ, McClain C, Karp CL, Klein AS, et al. Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats. Am J Physiol. 1996;270:G909–18.

    PubMed  Google Scholar 

  225. Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, et al. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005;106:756–63.

    Article  PubMed  Google Scholar 

  226. Chamberlain J, Yamagami T, Colletti E, Theise ND, Desai J, et al. Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep. Hepatology. 2007;46:1935–45.

    Article  PubMed  Google Scholar 

  227. Meier RPH, Muller YD, Morel P, Gonelle-Gispert C, Buhler LH. Transplantation of mesenchymal stem cells for the treatment of liver diseases, is there enough evidence? Stem Cell Res. 2013;11:1348–64.

    Article  PubMed  Google Scholar 

  228. Bae SH. Clinical application of stem cells in liver diseases. Korean J Hepatol. 2008;14:309–17.

    Article  PubMed  Google Scholar 

  229. Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 2006;130:1807–21.

    Article  PubMed  Google Scholar 

  230. Khalili S, Liu YN, Kornete M, Roescher N, Kodama S, et al. Mesenchymal stromal cells improve salivary function and reduce lymphocytic infiltrates in mice with Sjogren’s-like disease. PLoS One. 2012;7:e38615.

    Article  PubMed  PubMed Central  Google Scholar 

  231. Coppes RP, Zeilstra LJW, Kampinga HH, Konings AWT. Early to late sparing of radiation damage to the parotid gland by adrenergic and muscarinic receptor agonists. Br J Cancer. 2001;85:1055–63.

    Article  PubMed  PubMed Central  Google Scholar 

  232. Konings AWT, Faber H, Cotteleer F, Vissink A, Coppes RP. Secondary radiation damage as the main cause for unexpected volume effects: a histopathologic study of the parotid gland. Int J Radiat Oncol Biol Phys. 2006;64:98–105.

    Article  PubMed  Google Scholar 

  233. Jeong J, Baek H, Kim YJ, Choi Y, Lee H, et al. Human salivary gland stem cells ameliorate hyposalivation of radiation-damaged rat salivary glands. Exp Mol Med. 2013;45:e58.

    Article  PubMed  PubMed Central  Google Scholar 

  234. Lombaert IMA, Brunsting JF, Wierenga PK, Faber H, Stokman MA, et al. Rescue of salivary gland function after stem cell transplantation in irradiated glands. PLoS One. 2008;3:e2063.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, et al. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med. 2003;9:596–603.

    Article  PubMed  Google Scholar 

  236. Nakatsuji N, Nakajima F, Tokunaga K. HLA-haplotype banking and iPS cells. Nat Biotechnol. 2008;26:739–40.

    Article  PubMed  Google Scholar 

  237. Lanza RP, Hayes JL, Chick WL. Encapsulated cell technology. Nat Biotechnol. 1996;14:1107–11.

    Article  PubMed  Google Scholar 

  238. Dean SK, Yulyana Y, Williams G, Sidhu KS, Tuch BE. Differentiation of encapsulated embryonic stem cells after transplantation. Transplantation. 2006;82:1175–84.

    Article  PubMed  Google Scholar 

  239. Selmani Z, Naji A, Gaiffe E, Obert L, Tiberghien P, et al. HLA-G is a crucial immunosuppressive molecule secreted by adult human mesenchymal stem cells. Transplantation. 2009;87:S62–6.

    Article  PubMed  Google Scholar 

  240. Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SW. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol. 2013;91:32–9.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work is supported by the NIH/NIDCR grants DE019644 and DE025726 (S.C.). The authors thank Dr. Kathleen M. Berg for critical proofreading.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL, 32610, USA

    Seunghee Cha DDS, PhD

  2. Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-3280, USA

    Yun-Jong Park

Authors
  1. Yun-Jong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seunghee Cha DDS, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seunghee Cha DDS, PhD .

Editor information

Editors and Affiliations

  1. Oral and Maxillofacial Diagnostic Sciences, University of Florida, Gainesville, Florida, USA

    Seunghee Cha

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Park, YJ., Cha, S. (2017). Directed Cell Differentiation by Inductive Signals in Salivary Gland Regeneration: Lessons Learned from Pancreas and Liver Regeneration. In: Cha, S. (eds) Salivary Gland Development and Regeneration. Springer, Cham. https://doi.org/10.1007/978-3-319-43513-8_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-43513-8_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-43511-4

  • Online ISBN: 978-3-319-43513-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation