Skip to main content

Pancreatic Stem Cells: From Possible to Probable

Abstract

Type 1 and some forms of type 2 diabetes mellitus are caused by deficiency of insulin-secretory islet β cells. An ideal treatment for these diseases would therefore be to replace β cells, either by transplanting donated islets or via endogenous regeneration (and controlling the autoimmunity in type 1 diabetes). Unfortunately, the poor availability of donor islets has severely restricted the broad clinical use of islet transplantation. The ability to differentiate embryonic stem cells into insulin-expressing cells initially showed great promise, but the generation of functional β cells has proven extremely difficult and far slower than originally hoped. Pancreatic stem cells (PSC) or transdifferentiation of other cell types in the pancreas may hence provide an alternative renewable source of surrogate β cells. However, the existence of PSC has been hotly debated for many years. In this review, we will discuss the latest development and future perspectives of PSC research, giving readers an overview of this controversial but important area.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Lock, L. T., & Tzanakakis, E. S. (2007). Stem/progenitor cell sources of insulin-producing cells for the treatment of diabetes. Tissue Engineering, 13, 1399–1412.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Ramalho-Santos, M., & Willenbring, H. (2007). On the origin of the term “stem cell”. Cell Stem Cell, 1, 35–38.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154–156.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Martin, G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences of the United States of America, 78, 7634–7638.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Tesar, P. J., Chenoweth, J. G., Brook, F. A., et al. (2007). New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature, 448, 196–199.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Brons, I. G., Smithers, L. E., Trotter, M. W., et al. (2007). Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature, 448, 191–195.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Shamblott, M. J., Axelman, J., Wang, S., et al. (1998). Derivation of pluripotent stem cells from cultured human primordial germ cells. Proceedings of the National Academy of Sciences of the United States of America, 95, 13726–13731.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Kanatsu-Shinohara, M., Inoue, K., Lee, J., et al. (2004). Generation of pluripotent stem cells from neonatal mouse testis. Cell, 119, 1001–1012.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Guan, K., Nayernia, K., Maier, L. S., et al. (2006). Pluripotency of spermatogonial stem cells from adult mouse testis. Nature, 440, 1199–1203.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Aoi, T., Yae, K., Nakagawa, M., et al. (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science, 321, 699–702.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Hanna, J., Markoulaki, S., Schorderet, P., et al. (2008). Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell, 133, 250–264.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Park, I. H., Zhao, R., West, J. A., et al. (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature, 451, 141–146.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Ramiya, V. K., Maraist, M., Arfors, K. E., Schatz, D. A., Peck, A. B., & Cornelius, J. G. (2000). Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nature Medicine, 6, 278–282.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Dor, Y., Brown, J., Martinez, O. I., & Melton, D. A. (2004). Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature, 429, 41–46.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Pictet, R. L., Clark, W. R., Williams, R. H., & Rutter, W. J. (1972). An ultrastructural analysis of the developing embryonic pancreas. Developmental Biology, 29, 436–467.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Pan, F. C., & Wright, C. (2011). Pancreas organogenesis: From bud to plexus to gland. Developmental Dynamics, 240, 530–565.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Seymour, P. A., & Sander, M. (2011). Historical perspective: Beginnings of the beta-cell: Current perspectives in beta-cell development. Diabetes, 60, 364–376.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Piper, K., Brickwood, S., Turnpenny, L. W., et al. (2004). Beta cell differentiation during early human pancreas development. Journal of Endocrinology, 181, 11–23.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Herrera, P. L., Huarte, J., Sanvito, F., Meda, P., Orci, L., & Vassalli, J. D. (1991). Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development, 113, 1257–1265.

    PubMed  CAS  Google Scholar 

  21. 21.

    Richardson, M. K., Hanken, J., Gooneratne, M. L., et al. (1997). There is no highly conserved embryonic stage in the vertebrates: Implications for current theories of evolution and development. Anatomy and Embryology (Berl), 196, 91–106.

    Article  CAS  Google Scholar 

  22. 22.

    Fougerousse, F., Bullen, P., Herasse, M., et al. (2000). Human-mouse differences in the embryonic expression patterns of developmental control genes and disease genes. Human Molecular Genetics, 9, 165–173.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    De Krijger, R. R., Aanstoot, H. J., Kranenburg, G., Reinhard, M., Visser, W. J., & Bruining, G. J. (1992). The midgestational human fetal pancreas contains cells coexpressing islet hormones. Developmental Biology, 153, 368–375.

    PubMed  Article  Google Scholar 

  24. 24.

    Lukinius, A., Ericsson, J. L., Grimelius, L., & Korsgren, O. (1992). Ultrastructural studies of the ontogeny of fetal human and porcine endocrine pancreas, with special reference to colocalization of the four major islet hormones. Developmental Biology, 153, 376–385.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Polak, M., Bouchareb-Banaei, L., Scharfmann, R., & Czernichow, P. (2000). Early pattern of differentiation in the human pancreas. Diabetes, 49, 225–232.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Gu, G., Dubauskaite, J., & Melton, D. A. (2002). Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development, 129, 2447–2457.

    PubMed  CAS  Google Scholar 

  27. 27.

    Ohneda, K., Mirmira, R. G., Wang, J., Johnson, J. D., & German, M. S. (2000). The homeodomain of PDX-1 mediates multiple protein-protein interactions in the formation of a transcriptional activation complex on the insulin promoter. Molecular and Cellular Biology, 20, 900–911.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Zhou, Q., Law, A. C., Rajagopal, J., Anderson, W. J., Gray, P. A., & Melton, D. A. (2007). A multipotent progenitor domain guides pancreatic organogenesis. Developmental Cell, 13, 103–114.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Seymour, P. A., Freude, K. K., Tran, M. N., et al. (2007). SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proceedings of the National Academy of Sciences of the United States of America, 104, 1865–1870.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Lyttle, B. M., Li, J., Krishnamurthy, M., et al. (2008). Transcription factor expression in the developing human fetal endocrine pancreas. Diabetologia, 51, 1169–1180.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Jeon, J., Correa-Medina, M., Ricordi, C., Edlund, H., & Diez, J. A. (2009). Endocrine cell clustering during human pancreas development. Journal of Histochemistry and Cytochemistry, 57, 811–824.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Gradwohl, G., Dierich, A., LeMeur, M., & Guillemot, F. (2000). Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proceedings of the National Academy of Sciences of the United States of America, 97, 1607–1611.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Xu, X., D'Hoker, J., Stange, G., et al. (2008). Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell, 132, 197–207.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Schwitzgebel, V. M., Scheel, D. W., Conners, J. R., et al. (2000). Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development, 127, 3533–3542.

    PubMed  CAS  Google Scholar 

  35. 35.

    Jensen, J., Heller, R. S., Funder-Nielsen, T., et al. (2000). Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: A role for the notch pathway in repression of premature differentiation. Diabetes, 49, 163–176.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Oliver-Krasinski, J. M., Kasner, M. T., Yang, J., et al. (2009). The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice. Journal of Clinical Investigation, 119, 1888–1898.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Desgraz, R., Herrera, P. L. (2009). Pancreatic neurogenin 3-expressing cells are unipotent islet precursors. Development.

  38. 38.

    Miyatsuka, T., Kosaka, Y., Kim, H., & German, M. S. (2011). Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a. Proceedings of the National Academy of Sciences of the United States of America, 108, 185–190.

    PubMed  Article  Google Scholar 

  39. 39.

    Bonner-Weir, S., & Sharma, A. (2002). Pancreatic stem cells. The Journal of Pathology, 197, 519–526.

    PubMed  Article  Google Scholar 

  40. 40.

    Ryan, E. A., Lakey, J. R., Paty, B. W., et al. (2002). Successful islet transplantation: Continued insulin reserve provides long-term glycemic control. Diabetes, 51, 2148–2157.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Ryan, E. A., Paty, B. W., Senior, P. A., et al. (2005). Five-year follow-up after clinical islet transplantation. Diabetes, 54, 2060–2069.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Wagers, A. J., Sherwood, R. I., Christensen, J. L., & Weissman, I. L. (2002). Little evidence for developmental plasticity of adult hematopoietic stem cells. Science, 297, 2256–2259.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Bonner-Weir, S. (2000). Life and death of the pancreatic beta cells. Trends in Endocrinology and Metabolism, 11, 375–378.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Parsons, J. A., Brelje, T. C., & Sorenson, R. L. (1992). Adaptation of islets of Langerhans to pregnancy: Increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology, 130, 1459–1466.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Hellman, B. (1960). The islets of Langerhans in the rat during pregnancy and lactation, with special reference to the changes in the B/A cell ratio. Acta Obstetricia et Gynecologica Scandinavica, 39, 331–342.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Van Assche, F. A. (1974). Quantitative morphologic and histoenzymatic study of the endocrine pancreas in nonpregnant and pregnant rats. American Journal of Obstetrics and Gynecology, 118, 39–41.

    PubMed  Google Scholar 

  47. 47.

    Karnik, S. K., Chen, H., McLean, G. W., et al. (2007). Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus. Science, 318, 806–809.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Van Assche, F. A., Aerts, L., & De Prins, F. (1978). A morphological study of the endocrine pancreas in human pregnancy. British Journal of Obstetrics and Gynaecology, 85, 818–820.

    PubMed  Article  Google Scholar 

  49. 49.

    Nielsen, J. H., Svensson, C., Galsgaard, E. D., Moldrup, A., & Billestrup, N. (1999). Beta cell proliferation and growth factors. Journal of Molecular Medicine, 77, 62–66.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Rieck, S., & Kaestner, K. H. (2010). Expansion of beta-cell mass in response to pregnancy. Trends in Endocrinology and Metabolism, 21, 151–158.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Kim, H., Toyofuku, Y., Lynn, F. C., et al. (2010). Serotonin regulates pancreatic beta cell mass during pregnancy. Nature Medicine, 16, 804–808.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Butler, A. E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R. A., & Butler, P. C. (2003). Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 52, 102–110.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Butler, A. E., Janson, J., Soeller, W. C., & Butler, P. C. (2003). Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: Evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes, 52, 2304–2314.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Matveyenko, A. V., Veldhuis, J. D., & Butler, P. C. (2006). Mechanisms of impaired fasting glucose and glucose intolerance induced by an approximate 50% pancreatectomy. Diabetes, 55, 2347–2356.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Stagner, J. I., & Samols, E. (1991). Deterioration of islet beta-cell function after hemipancreatectomy in dogs. Diabetes, 40, 1472–1479.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Robertson, R. P., Lanz, K. J., Sutherland, D. E., & Seaquist, E. R. (2002). Relationship between diabetes and obesity 9 to 18 years after hemipancreatectomy and transplantation in donors and recipients. Transplantation, 73, 736–741.

    PubMed  Article  Google Scholar 

  57. 57.

    Nir, T., Melton, D. A., & Dor, Y. (2007). Recovery from diabetes in mice by beta cell regeneration. Journal of Clinical Investigation, 117, 2553–2561.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Brennand, K., Huangfu, D., & Melton, D. (2007). All beta cells contribute equally to islet growth and maintenance. PLoS Biology, 5, e163.

    PubMed  Article  Google Scholar 

  59. 59.

    Gupta, R. K., Gao, N., Gorski, R. K., et al. (2007). Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes & Development, 21, 756–769.

    Article  CAS  Google Scholar 

  60. 60.

    Georgia, S., & Bhushan, A. (2004). Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. Journal of Clinical Investigation, 114, 963–968.

    PubMed  CAS  Google Scholar 

  61. 61.

    Teta, M., Rankin, M. M., Long, S. Y., Stein, G. M., & Kushner, J. A. (2007). Growth and regeneration of adult beta cells does not involve specialized progenitors. Developmental Cell, 12, 817–826.

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Jiang, F. X., Mehta, M., & Morahan, G. (2010). Quantification of insulin gene expression during development of pancreatic islet cells. Pancreas, 39, 201–208.

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Hara, M., Dizon, R. F., Glick, B. S., et al. (2006). Imaging pancreatic beta-cells in the intact pancreas. American Journal of Physiology, Endocrinology and Metabolism, 290, E1041–E1047.

    Article  CAS  Google Scholar 

  64. 64.

    Alpert, S., Hanahan, D., & Teitelman, G. (1988). Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell, 53, 295–308.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Cornelius, J. G., Tchernev, V., Kao, K. J., & Peck, A. B. (1997). In vitro-generation of islets in long-term cultures of pluripotent stem cells from adult mouse pancreas. Hormone and Metabolic Research, 29, 271–277.

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Suzuki, A., Oyama, K., Fukao, K., Nakauchi, H., & Taniguchi, H. (2002). Establishment of clonal colony-forming assay system for pancreatic stem/progenitor cells. Cell Transplantation, 11, 451–453.

    PubMed  Google Scholar 

  67. 67.

    Zulewski, H., Abraham, E. J., Gerlach, M. J., et al. (2001). Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes, 50, 521–533.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Seaberg, R. M., Smukler, S. R., Kieffer, T. J., et al. (2004). Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nature Biotechnology, 22, 1115–1124.

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Suzuki, A., Nakauchi, H., & Taniguchi, H. (2004). Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. Diabetes, 53, 2143–2152.

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Jiang, F. X., Stanley, E. G., Gonez, L. J., & Harrison, L. C. (2002). Bone morphogenetic proteins promote development of fetal pancreas epithelial colonies containing insulin-positive cells. Journal of Cell Science, 115, 753–760.

    PubMed  CAS  Google Scholar 

  71. 71.

    Jiang, F. X., & Harrison, L. C. (2005). Convergence of bone morphogenetic protein and laminin-1 signaling pathways promotes proliferation and colony formation by fetal mouse pancreatic cells. Experimental Cell Research, 308, 114–122.

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Jiang, F. X., & Harrison, L. C. (2005). Laminin-1 and epidermal growth factor family members co-stimulate fetal pancreas cell proliferation and colony formation. Differentiation, 73, 45–49.

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Bonner-Weir, S., Taneja, M., Weir, G. C., et al. (2000). In vitro cultivation of human islets from expanded ductal tissue. Proceedings of the National Academy of Sciences of the United States of America, 97, 7999–8004.

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Seeberger, K. L., Dufour, J. M., Shapiro, A. M., Lakey, J. R., Rajotte, R. V., & Korbutt, G. S. (2006). Expansion of mesenchymal stem cells from human pancreatic ductal epithelium. Laboratory Investigation, 86, 141–153.

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Bonner-Weir, S., Inada, A., Yatoh, S., et al. (2008). Transdifferentiation of pancreatic ductal cells to endocrine beta-cells. Biochemical Society Transactions, 36, 353–356.

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Inada, A., Nienaber, C., Katsuta, H., et al. (2008). Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proceedings of the National Academy of Sciences of the United States of America, 105, 19915–19919.

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Solar, M., Cardalda, C., Houbracken, I., et al. (2009). Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Developmental Cell, 17, 849–860.

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Haumaitre, C., Barbacci, E., Jenny, M., Ott, M. O., Gradwohl, G., & Cereghini, S. (2005). Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proceedings of the National Academy of Sciences of the United States of America, 102, 1490–1495.

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Haumaitre, C., Fabre, M., Cormier, S., Baumann, C., Delezoide, A. L., & Cereghini, S. (2006). Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations. Human Molecular Genetics, 15, 2363–2375.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Hao, E., Tyrberg, B., Itkin-Ansari, P., et al. (2006). Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas. Nature Medicine, 12, 310–316.

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Minami, K., Okuno, M., Miyawaki, K., et al. (2005). Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells. Proceedings of the National Academy of Sciences of the United States of America, 102, 15116–15121.

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Baeyens, L., De Breuck, S., Lardon, J., Mfopou, J. K., Rooman, I., & Bouwens, L. (2005). In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells. Diabetologia, 48, 49–57.

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    Minami, K., Okano, H., Okumachi, A., & Seino, S. (2008). Role of cadherin-mediated cell-cell adhesion in pancreatic exocrine-to-endocrine transdifferentiation. Journal of Biological Chemistry, 283, 13753–13761.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J., & Melton, D. A. (2008). In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature, 455, 627–632.

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Desai, B. M., Oliver-Krasinski, J., De Leon, D. D., et al. (2007). Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. Journal of Clinical Investigation, 117, 971–977.

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Abraham, E. J., Leech, C. A., Lin, J. C., Zulewski, H., & Habener, J. F. (2002). Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology, 143, 3152–3161.

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Lardon, J., Rooman, I., & Bouwens, L. (2002). Nestin expression in pancreatic stellate cells and angiogenic endothelial cells. Histochemistry and Cell Biology, 117, 535–540.

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Selander, L., & Edlund, H. (2002). Nestin is expressed in mesenchymal and not epithelial cells of the developing mouse pancreas. Mechanisms of Development, 113, 189–192.

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Gershengorn, M. C., Hardikar, A. A., Wei, C., Geras-Raaka, E., Marcus-Samuels, B., & Raaka, B. M. (2004). Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science, 306, 2261–2264.

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Chase, L. G., Ulloa-Montoya, F., Kidder, B. L., & Verfaillie, C. M. (2007). Islet-derived fibroblast-like cells are not derived via epithelial-mesenchymal transition from Pdx-1 or insulin-positive cells. Diabetes, 56, 3–7.

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Russ, H. A., Bar, Y., Ravassard, P., & Efrat, S. (2008). In vitro proliferation of cells derived from adult human beta-cells revealed by cell-lineage tracing. Diabetes, 57, 1575–1583.

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Smukler, S. R., Arntfield, M. E., Razavi, R., et al. (2011). The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell, 8, 281–293.

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Daniel, C. P., Ponting, I. L., & Dexter, T. M. (1989). Growth and development of haemopoietic cells: A deterministic process? Hämatologie und Bluttransfusion, 32, 172–177.

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Dexter, T. M. (1989). Regulation of hemopoietic cell growth and development: Experimental and clinical studies. Leukemia, 3, 469–474.

    PubMed  CAS  Google Scholar 

  95. 95.

    Gu, G., Wells, J. M., Dombkowski, D., Preffer, F., Aronow, B., & Melton, D. A. (2004). Global expression analysis of gene regulatory pathways during endocrine pancreatic development. Development, 131, 165–179.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are supported by grants from Juvenile Diabetes Research Foundational International (4-2006-1025), the Diabetes Research Foundation of Western Australia, the University of Western Australia, National Health and Medical Research Council Program Grant (53000400) and the Medical Research Foundation of Royal Perth Hospital.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Fang-Xu Jiang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jiang, FX., Morahan, G. Pancreatic Stem Cells: From Possible to Probable. Stem Cell Rev and Rep 8, 647–657 (2012). https://doi.org/10.1007/s12015-011-9333-8

Download citation

Keywords

  • Pancreatic stem cells
  • Regeneration
  • Self-renewal
  • Clonogenesis
  • Differentiation