Surgery Today

, Volume 46, Issue 6, pp 633–640 | Cite as

Pancreatic regeneration: basic research and gene regulation

  • Kenji Okita
  • Toru Mizuguchi
  • Ota Shigenori
  • Masayuki Ishii
  • Toshihiko Nishidate
  • Tomomi Ueki
  • Makoto Meguro
  • Yasutoshi Kimura
  • Naoki Tanimizu
  • Norihisa Ichinohe
  • Toshihiko Torigoe
  • Takashi Kojima
  • Toshihiro Mitaka
  • Noriyuki Sato
  • Norimasa Sawada
  • Koichi Hirata
Review Article
First Online:
Received:
Accepted:

Abstract

Pancreatic regeneration (PR) is an interesting phenomenon that could provide clues as to how the control of diabetes mellitus might be achieved. Due to the different regenerative abilities of the pancreas and liver, the molecular mechanism responsible for PR is largely unknown. In this review, we describe five representative murine models of PR and thirteen humoral mitogens that stimulate β-cell proliferation. We also describe pancreatic ontogenesis, including the molecular transcriptional differences between α-cells and β-cells. Furthermore, we review 14 murine models which carry defects in genes related to key transcription factors for pancreatic ontogenesis to gain further insight into pancreatic development.

Keywords

Pancreatic regeneration Transcriptional factors Gene regulation 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

Part of this study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (No.24659592) to T. Mizuguchi, T. Torigoe, N. Sato, and K. Hirata. Part of this study was also supported by a Health Labour Sciences Research Grant from the Ministry of Health, Labour, and Welfare (No. 2601023) to T. Mizuguchi, T. Torigoe, K. Hirata, and N. Sato.

References

  1. 1.
    Yagi H, Soto-Gutierrez A, Kitagawa Y. Whole-organ re-engineering: a regenerative medicine approach in digestive surgery for organ replacement. Surg Today. 2013;43:587–94.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Takahashi K, Murata S, Ohkohchi N. Novel therapy for liver regeneration by increasing the number of platelets. Surg Today. 2013;43:1081–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Peng HS, Xu XH, Zhang R, He XY, Wang XX, Wang WH, et al. Multiple low doses of erythropoietin delay the proliferation of hepatocytes but promote liver function in a rat model of subtotal hepatectomy. Surg Today. 2014;44:1109–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Menge BA, Tannapfel A, Belyaev O, Drescher R, Muller C, Uhl W, et al. Partial pancreatectomy in adult humans does not provoke beta-cell regeneration. Diabetes. 2008;57:142–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Scow RO. Total pancreatectomy in the rat: operation, effects, and postoperative care. Endocrinology. 1957;60:359–67.CrossRefPubMedGoogle Scholar
  6. 6.
    Houry S, Huguier M. Total splenopancreatectomy in the rat. Technical report. Eur Surg Res. 1983;15:328–31.CrossRefPubMedGoogle Scholar
  7. 7.
    Migliorini RH. Two-stage procedure for total pancreatectomy in the rat. Diabetes. 1970;19:694–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Wenger JM, Meyer P, Morel DR, Costabella PM, Rohner A. Radical splenopancreatectomy with duodenal loop conservation in rats. J Surg Res. 1990;49:361–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Richards C, Fitzgerald PJ, Carol B, Rosenstock L, Lipkin L. Segmental division of the rat pancreas for experimental procedures. Lab Invest. 1964;13:1303–21.PubMedGoogle Scholar
  10. 10.
    Pearson KW, Scott D, Torrance B. Effects of partial surgical pancreatectomy in rats. I. Pancreatic regeneration. Gastroenterology. 1977;72:469–73.PubMedGoogle Scholar
  11. 11.
    Cavelti-Weder C, Shtessel M, Reuss JE, Jermendy A, Yamada T, Caballero F, et al. Pancreatic duct ligation after almost complete beta-cell loss: exocrine regeneration but no evidence of beta-cell regeneration. Endocrinology. 2013;154:4493–502.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Xu X, D’Hoker J, Stange G, Bonne S, De Leu N, Xiao X, et al. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 2008;132:197–207.CrossRefPubMedGoogle Scholar
  13. 13.
    Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R, et al. Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci. 2008;105:19915–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Pan FC, Bankaitis ED, Boyer D, Xu X, Van de Casteele M, Magnuson MA, et al. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development. 2013;140:751–64.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Shing Y, Christofori G, Hanahan D, Ono Y, Sasada R, Igarashi K, et al. Betacellulin: a mitogen from pancreatic beta cell tumors. Science. 1993;259:1604–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Yamamoto K, Miyagawa J, Waguri M, Sasada R, Igarashi K, Li M, et al. Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion. Diabetes. 2000;49:2021–7.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedGoogle Scholar
  18. 18.
    Song SY, Gannon M, Washington MK, Scoggins CR, Meszoely IM, Goldenring JR, et al. Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha. Gastroenterology. 1999;117:1416–26.CrossRefPubMedGoogle Scholar
  19. 19.
    Krakowski ML, Kritzik MR, Jones EM, Krahl T, Lee J, Arnush M, et al. Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes. J Endocrinol. 1999;162:167–75.CrossRefPubMedGoogle Scholar
  20. 20.
    Alvarez-Perez JC, Ernst S, Demirci C, Casinelli GP, Mellado-Gil JM, Rausell-Palamos F, et al. Hepatocyte growth factor/c-Met signaling is required for beta-cell regeneration. Diabetes. 2014;63:216–23.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999;48:2270–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Greig NH, Holloway HW, De Ore KA, Jani D, Wang Y, Zhou J, et al. Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia. 1999;42:45–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Drucker DJ. Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes. 2013;62:3316–23.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34(Suppl 2):S279–84.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rooman I, Lardon J, Bouwens L. Gastrin stimulates beta-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes. 2002;51:686–90.CrossRefPubMedGoogle Scholar
  26. 26.
    Suarez-Pinzon WL, Power RF, Yan Y, Wasserfall C, Atkinson M, Rabinovitch A. Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice. Diabetes. 2008;57:3281–8.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pittenger GL, Vinik AI, Rosenberg L. The partial isolation and characterization of ilotropin, a novel islet-specific growth factor. Adv Exp Med Biol. 1992;321:123–130 (discussion 131–122).Google Scholar
  28. 28.
    Dungan KM, Buse JB, Ratner RE. Effects of therapy in type 1 and type 2 diabetes mellitus with a peptide derived from islet neogenesis associated protein (INGAP). Diabetes Metab Res Rev. 2009;25:558–65.CrossRefPubMedGoogle Scholar
  29. 29.
    Shah KA, Patel MB, Patel RJ, Parmar PK. Mangifera indica (mango). Pharmacogn Rev. 2010;4:42–8.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tyutyulkova N, Tuneva S, Gorantcheva U, Tanev G, Zhivkov V, Chelibonova-Lorer H, et al. Hepatoprotective effect of silymarin (carsil) on liver of D-galactosamine treated rats. Biochemical and morphological investigations. Methods Find Exp Clin Pharmacol. 1981;3:71–7.PubMedGoogle Scholar
  31. 31.
    Vargas-Mendoza N, Madrigal-Santillan E, Morales-Gonzalez A, Esquivel-Soto J, Esquivel-Chirino C, Garcia-Luna YG-RM, et al. Hepatoprotective effect of silymarin. World J Hepatol. 2014;6:144–9.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Soto C, Raya L, Perez J, Gonzalez I, Perez S. Silymarin induces expression of pancreatic Nkx6.1 transcription factor and beta-cells neogenesis in a pancreatectomy model. Molecules. 2014;19:4654–68.CrossRefPubMedGoogle Scholar
  33. 33.
    Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, et al. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci. 2012;109:19751–6.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yi P, Park JS, Melton DA. Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell. 2013;153:747–58.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, et al. Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci. 2013;110:16109–14.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Guney MA, Gannon M. Pancreas cell fate. Birth Defects Res C Embryo Today. 2009;87:232–48.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kim SK, Hebrok M, Melton DA. Notochord to endoderm signaling is required for pancreas development. Development. 1997;124:4243–52.PubMedGoogle Scholar
  38. 38.
    Hebrok M, Kim SK, Melton DA. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 1998;12:1705–13.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    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. 2000;97:1607–11.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Haumaitre C, Barbacci E, Jenny M, Ott MO, Gradwohl G, Cereghini S. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc Natl Acad Sci. 2005;102:1490–5.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Artner I, Blanchi B, Raum JC, Guo M, Kaneko T, Cordes S, et al. MafB is required for islet beta cell maturation. Proc Natl Acad Sci. 2007;104:3853–8.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Slack JM. Developmental biology of the pancreas. Development. 1995;121:1569–80.PubMedGoogle Scholar
  43. 43.
    Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994;371:606–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Dutta S, Bonner-Weir S, Montminy M, Wright C. Regulatory factor linked to late-onset diabetes? Nature. 1998;392:560.CrossRefPubMedGoogle Scholar
  45. 45.
    Rose SD, Swift GH, Peyton MJ, Hammer RE, MacDonald RJ. The role of PTF1-P48 in pancreatic acinar gene expression. J Biol Chem. 2001;276:44018–26.CrossRefPubMedGoogle Scholar
  46. 46.
    Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CV. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet. 2002;32:128–34.CrossRefPubMedGoogle Scholar
  47. 47.
    Krapp A, Knofler M, Ledermann B, Burki K, Berney C, Zoerkler N, et al. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 1998;12:3752–63.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Chuang PT, Kornberg TB. On the range of hedgehog signaling. Curr Opin Genet Dev. 2000;10:515–22.CrossRefPubMedGoogle Scholar
  49. 49.
    Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 2000;127:2763–72.PubMedGoogle Scholar
  50. 50.
    van Tuyl M, Groenman F, Wang J, Kuliszewski M, Liu J, Tibboel D, et al. Angiogenic factors stimulate tubular branching morphogenesis of sonic hedgehog-deficient lungs. Dev Biol. 2007;303:514–26.CrossRefPubMedGoogle Scholar
  51. 51.
    Hebrok M, Kim SK, St Jacques B, McMahon AP, Melton DA. Regulation of pancreas development by hedgehog signaling. Development. 2000;127:4905–13.PubMedGoogle Scholar
  52. 52.
    Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, et al. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet. 1997;17:384–5.CrossRefPubMedGoogle Scholar
  53. 53.
    Ravassard P, Chatail F, Mallet J, Icard-Liepkalns C. Relax, a novel rat bHLH transcriptional regulator transiently expressed in the ventricular proliferating zone of the developing central nervous system. J Neurosci Res. 1997;48:146–58.CrossRefPubMedGoogle Scholar
  54. 54.
    Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 1997;11:2323–34.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997;15:106–10.CrossRefPubMedGoogle Scholar
  56. 56.
    Balderes DA, Magnuson MA, Sussel L. Nkx2.2: Cre knock-in mouse line: a novel tool for pancreas- and CNS-specific gene deletion. Genesis. 2013;51:844–51.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Sussel L, Kalamaras J, Hartigan-O’Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development. 1998;125:2213–21.PubMedGoogle Scholar
  58. 58.
    Dahl E, Koseki H, Balling R. Pax genes and organogenesis. Bioessays. 1997;19:755–65.CrossRefPubMedGoogle Scholar
  59. 59.
    Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 1997;386:399–402.CrossRefPubMedGoogle Scholar
  60. 60.
    May CL. The role of Islet-1 in the endocrine pancreas: Lessons from pancreas specific Islet-1 deficient mice. Islets. 2010;2:121–3.CrossRefPubMedGoogle Scholar
  61. 61.
    Pfaff SL, Mendelsohn M, Stewart CL, Edlund T, Jessell TM. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell. 1996;84:309–20.CrossRefPubMedGoogle Scholar
  62. 62.
    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.CrossRefPubMedGoogle Scholar
  63. 63.
    Lemaigre FP, Durviaux SM, Truong O, Lannoy VJ, Hsuan JJ, Rousseau GG. Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain. Proc Natl Acad Sci. 1996;93:9460–4.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Jacquemin P, Durviaux SM, Jensen J, Godfraind C, Gradwohl G, Guillemot F, et al. Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3. Mol Cell Biol. 2000;20:4445–54.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Blanchi B, Kelly LM, Viemari JC, Lafon I, Burnet H, Bevengut M, et al. MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth. Nat Neurosci. 2003;6:1091–100.CrossRefPubMedGoogle Scholar
  66. 66.
    Sosa-Pineda B. The gene Pax4 is an essential regulator of pancreatic beta-cell development. Mol Cells. 2004;18:289–94.PubMedGoogle Scholar
  67. 67.
    Kordowich S, Collombat P, Mansouri A, Serup P. Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage. BMC Dev Biol. 2011;11:52.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Collombat P, Hecksher-Sorensen J, Broccoli V, Krull J, Ponte I, Mundiger T, et al. The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development. 2005;132:2969–80.CrossRefPubMedGoogle Scholar
  69. 69.
    Price M, Lazzaro D, Pohl T, Mattei MG, Ruther U, Olivo JC, et al. Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain. Neuron. 1992;8:241–55.CrossRefPubMedGoogle Scholar
  70. 70.
    Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, et al. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development. 2000;127:5533–40.PubMedGoogle Scholar
  71. 71.
    Henseleit KD, Nelson SB, Kuhlbrodt K, Hennings JC, Ericson J, Sander M. NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas. Development. 2005;132:3139–49.CrossRefPubMedGoogle Scholar
  72. 72.
    Simpson TI, Price DJ. Pax6; a pleiotropic player in development. BioEssays. 2002;24:1041–51.CrossRefPubMedGoogle Scholar
  73. 73.
    St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature. 1997;387:406–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Vanderford NL. Regulation of beta-cell-specific and glucose-dependent MafA expression. Islets. 2011;3:35–7.CrossRefPubMedGoogle Scholar
  75. 75.
    Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 2005;25:4969–76.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Kenji Okita
    • 1
  • Toru Mizuguchi
    • 1
  • Ota Shigenori
    • 1
  • Masayuki Ishii
    • 1
  • Toshihiko Nishidate
    • 1
  • Tomomi Ueki
    • 1
  • Makoto Meguro
    • 1
  • Yasutoshi Kimura
    • 1
  • Naoki Tanimizu
    • 3
  • Norihisa Ichinohe
    • 3
  • Toshihiko Torigoe
    • 2
  • Takashi Kojima
    • 4
  • Toshihiro Mitaka
    • 3
  • Noriyuki Sato
    • 2
  • Norimasa Sawada
    • 5
  • Koichi Hirata
    • 6
  1. 1.Department of Surgery, Surgical OncologySapporo Medical UniversitySapporoJapan
  2. 2.Department of Pathology ISapporo Medical UniversitySapporoJapan
  3. 3.Department of Tissue Development and Regeneration, Research Institute for Frontier MedicineSapporo Medical UniversitySapporoJapan
  4. 4.Department of Cell Science, Research Institute for Frontier MedicineSapporo Medical UniversitySapporoJapan
  5. 5.Department of Surgical Pathology IISapporo Medical UniversitySapporoJapan
  6. 6.Department of SurgeryJR Sapporo HospitalSapporoJapan

Personalised recommendations