Journal of Hepato-Biliary-Pancreatic Sciences

, Volume 19, Issue 6, pp 594–599 | Cite as

Basics and applications of stem cells in the pancreas

Topics Stem cells in the Hepato-Biliary-Pancreas
  • 443 Downloads

Abstract

Enormous efforts have been made to establish pancreatic stem/progenitor cells as a source for regenerative medicine for the treatment of diabetes mellitus. In recent years, it has been recognized that the self-renewal of beta cells is the dominant process involved in postnatal beta-cell regeneration and expansion. Nevertheless, several in-vitro studies have suggested that ductal or as yet unidentified cells are candidates for pancreatic stem/progenitor cells that can differentiate into multilineage cells, including insulin+ cells. The question remains as to whether beta cells are generated postnatally from stem/progenitor cells other than pre-existing beta cells. Furthermore, mutated pancreatic stem cells are considered to be prospective candidates for cancer stem cells or tumor-initiating cells. This review highlights recent progress in pancreatic stem/progenitor cell research.

Keywords

Stem cell Progenitor cell Pdx1 Cancer stem cell 

References

  1. 1.
    Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Ramalho-Santos M, Willenbring H. On the origin of the term “stem cell”. Cell Stem Cell. 2007;1(1):35–8. doi:10.1016/j.stem.2007.05.013.PubMedCrossRefGoogle Scholar
  3. 3.
    Kushner JA, Weir GC, Bonner-Weir S. Ductal origin hypothesis of pancreatic regeneration under attack. Cell Metab. 2010;11(1):2–3. doi:10.1016/j.cmet.2009.12.005.PubMedCrossRefGoogle Scholar
  4. 4.
    Murtaugh LC. Stem cells and beta cells: the same, but different? Cell Stem Cell. 2011;8(3):244–5. doi:10.1016/j.stem.2011.02.010.PubMedCrossRefGoogle Scholar
  5. 5.
    Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008;322(5907):1490–4. doi:10.1126/science.1161431.PubMedCrossRefGoogle Scholar
  6. 6.
    Hebrok M, Kim SK, Melton DA. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 1998;12(11):1705–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science. 2001;294(5542):564–7. doi:10.1126/science.1064344.PubMedCrossRefGoogle Scholar
  8. 8.
    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(10):2447–57.PubMedGoogle Scholar
  9. 9.
    Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development. 1996;122(3):983–95.PubMedGoogle Scholar
  10. 10.
    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(1):106–10. doi:10.1038/ng0197-106.PubMedCrossRefGoogle Scholar
  11. 11.
    Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997;17(2):138–9. doi:10.1038/ng1097-138.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA. A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell. 2007;13(1):103–14. doi:10.1016/j.devcel.2007.06.001.PubMedCrossRefGoogle Scholar
  13. 13.
    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(1):128–34. doi:10.1038/ng959ng959.PubMedCrossRefGoogle Scholar
  14. 14.
    Habener JF, Kemp DM, Thomas MK. Minireview: transcriptional regulation in pancreatic development. Endocrinology. 2005;146(3):1025–34. doi:10.1210/en.2004-1576.PubMedCrossRefGoogle Scholar
  15. 15.
    Seymour PA, Freude KK, Tran MN, Mayes EE, Jensen J, Kist R, et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci USA. 2007;104(6):1865–70. doi:060921710410.1073/pnas.0609217104.PubMedCrossRefGoogle Scholar
  16. 16.
    Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318–30. doi:10.1056/NEJMoa061267.PubMedCrossRefGoogle Scholar
  17. 17.
    Oliver-Krasinski JM, Stoffers DA. On the origin of the beta cell. Genes Dev. 2008;22(15):1998–2021. doi:10.1101/gad.1670808.PubMedCrossRefGoogle Scholar
  18. 18.
    Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, Atkinson MA, et al. In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes. 2004;53(7):1721–32.PubMedCrossRefGoogle Scholar
  19. 19.
    Baeyens L, De Breuck S, Lardon J, Mfopou JK, Rooman I, Bouwens L. In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells. Diabetologia. 2005;48(1):49–57. doi:10.1007/s00125-004-1606-1.PubMedCrossRefGoogle Scholar
  20. 20.
    Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med. 2000;6(3):278–82. doi:10.1038/73128.PubMedCrossRefGoogle Scholar
  21. 21.
    Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 2004;429(6987):41–6. doi:10.1038/nature02520.PubMedCrossRefGoogle Scholar
  22. 22.
    Teta M, Rankin MM, Long SY, Stein GM, Kushner JA. Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell. 2007;12(5):817–26. doi:10.1016/j.devcel.2007.04.011.PubMedCrossRefGoogle Scholar
  23. 23.
    Solar M, Cardalda C, Houbracken I, Martin M, Maestro MA, De Medts N, et al. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell. 2009;17(6):849–60. doi:10.1016/j.devcel.2009.11.003.PubMedCrossRefGoogle Scholar
  24. 24.
    Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, et al. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA. 2000;97(14):7999–8004. doi:97/14/7999.PubMedCrossRefGoogle Scholar
  25. 25.
    Bonner-Weir S, Weir GC. New sources of pancreatic beta-cells. Nat Biotechnol. 2005;23(7):857–61. doi:10.1038/nbt1115.PubMedCrossRefGoogle Scholar
  26. 26.
    Reichert M, Rustgi AK. Pancreatic ductal cells in development, regeneration, and neoplasia. J Clin Invest. 2011;121(12):4572–8. doi:10.1172/JCI57131.PubMedCrossRefGoogle Scholar
  27. 27.
    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 USA. 2008;105(50):19915–9. doi:080580310510.1073/pnas.0805803105.PubMedCrossRefGoogle Scholar
  28. 28.
    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(2):197–207. doi:10.1016/j.cell.2007.12.015.PubMedCrossRefGoogle Scholar
  29. 29.
    Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov G, Asghar Z, Wheeler MB, et al. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol. 2004;22(9):1115–24. doi:10.1038/nbt1004.PubMedCrossRefGoogle Scholar
  30. 30.
    Smukler SR, Arntfield ME, Razavi R, Bikopoulos G, Karpowicz P, Seaberg R, et al. The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell. 2011;8(3):281–93. doi:10.1016/j.stem.2011.01.015.PubMedCrossRefGoogle Scholar
  31. 31.
    Suzuki A, Nakauchi H, Taniguchi H. Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. Diabetes. 2004;53(8):2143–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Oshima Y, Suzuki A, Kawashimo K, Ishikawa M, Ohkohchi N, Taniguchi H. Isolation of mouse pancreatic ductal progenitor cells expressing CD133 and c-Met by flow cytometric cell sorting. Gastroenterology. 2007;132(2):720–32. doi:S0016-5085(06)02482-610.1053/j.gastro.2006.11.027.PubMedCrossRefGoogle Scholar
  33. 33.
    D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 2005;23(12):1534–41. doi:10.1038/nbt1163.PubMedCrossRefGoogle Scholar
  34. 34.
    Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26(4):443–52. doi:10.1038/nbt1393.PubMedCrossRefGoogle Scholar
  35. 35.
    Kelly OG, Chan MY, Martinson LA, Kadoya K, Ostertag TM, Ross KG, et al. Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol. 2011;29(8):750–6. doi:10.1038/nbt.1931.PubMedCrossRefGoogle Scholar
  36. 36.
    Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L, et al. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol. 2009;5(4):258–65. doi:10.1038/nchembio.154.PubMedCrossRefGoogle Scholar
  37. 37.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. doi:10.1016/j.cell.2007.11.019.PubMedCrossRefGoogle Scholar
  38. 38.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi:10.1016/j.cell.2006.07.024.PubMedCrossRefGoogle Scholar
  39. 39.
    Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, et al. Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol. 2005;23(12):1542–50. doi:10.1038/nbt1167.PubMedCrossRefGoogle Scholar
  40. 40.
    Bhushan A, Itoh N, Kato S, Thiery JP, Czernichow P, Bellusci S, et al. Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development. 2001;128(24):5109–17.PubMedGoogle Scholar
  41. 41.
    Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T, et al. Fgf10 is essential for limb and lung formation. Nat Genet. 1999;21(1):138–41. doi:10.1038/5096.PubMedCrossRefGoogle Scholar
  42. 42.
    Collombat P, Hecksher-Sorensen J, Serup P, Mansouri A. Specifying pancreatic endocrine cell fates. Mech Dev. 2006;123(7):501–12. doi:10.1016/j.mod.2006.05.006.PubMedCrossRefGoogle Scholar
  43. 43.
    Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell. 2009;138(3):449–62. doi:10.1016/j.cell.2009.05.035.PubMedCrossRefGoogle Scholar
  44. 44.
    Schaffer AE, Freude KK, Nelson SB, Sander M. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell. 2010;18(6):1022–9. doi:10.1016/j.devcel.2010.05.015.PubMedCrossRefGoogle Scholar
  45. 45.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Hruban RH, Adsay NV, Albores-Saavedra J, Anver MR, Biankin AV, Boivin GP, et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res. 2006;66(1):95–106. doi:66/1/9510.1158/0008-5472.CAN-05-2168.PubMedCrossRefGoogle Scholar
  47. 47.
    Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006;20(10):1218–49. doi:10.1101/gad.1415606.PubMedCrossRefGoogle Scholar
  48. 48.
    Morris JPT, Wang SC, Hebrok M (2010) KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 10(10):683–95. doi:10.1038/nrc2899.Google Scholar

Copyright information

© Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012

Authors and Affiliations

  1. 1.Department of Regenerative Medicine, Graduate School of MedicineYokohama City UniversityYokohamaJapan

Personalised recommendations