Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats (original) (raw)

Summary

We investigated the growth of islet beta and alpha cells in adult rats which had undergone partial pancreatic duct ligation. Whereas the non-ligated head portion of the pancreas remained unaffected in terms of histology and cell population dynamics, the ligated tail part of the pancreas showed pronounced changes in histology and cell growth. These changes included replacement of exocrine acini by ductal complexes and significant growth of islet cells. Using immunocytochemistry and morphometry, we found that the beta-cell population had nearly doubled within 1 week and that a smaller, but also significant growth of the alpha-cell population had occurred. In addition, small islets and islet-cell clusters were more numerous in the pancreatic tail, indicating islet neogenesis. The bromodeoxyuridine (BrdU) pulse labelling index of beta and alpha cells increased five fold and threefold, respectively, in the tail. However, the observed beta-cell labelling index remained below 1% which was largely insufficient to explain the increased number of beta cells. This indicates that recruitment from a proliferating stem-cell compartment was the main source for the beta-cell hyperplasia. A tenfold-elevated BrdU labelling index (18%) was observed in the duct-cell compartment which was identified by specific immunostaining for cytokeratin 20. Transitional cytodifferentiation forms between duct cells expressing cytokeratin 20 and beta cells expressing insulin, or alpha cells expressing glucagon, were demonstrated by double immunostaining. Pancreatic duct ligation also induced the expression of the beta-cell-specific glucose transporter type 2 (GLUT-2) in duct cells, indicating their metaplastic state. We concluded that in this adult rat model, the proliferation and differentiation of exocrine duct cells represents the major mechanism of endocrine beta-cell neogenesis. Our study thus demonstrates that in normal adult rats islet-cell neogenesis can be reactivated by stimulation of pancreatic duct cells.

Article PDF

Similar content being viewed by others

Abbreviations

BrdU:

Bromodeoxyuridine

CK20:

cytokeratin 20

GLUT-2:

glucose transporter type 2

LI:

labelling index

CBR:

cell birth rate

References

  1. Logothetopoulos J (1972) Islet cell regeneration and neogenesis. In: Steiner DF, Freinkel N (eds) Handbook of physiology, sect 7, Endocrinology, vol 1. American Physiological Society, Washington, pp 67–76
    Google Scholar
  2. Hellerström C (1984) The life story of the pancreatic Β cell. Diabetologia 26: 393–400
    PubMed Google Scholar
  3. Swenne I (1992) Pancreatic beta-cell growth and diabetes mellitus. Diabetologia 35: 193–201
    PubMed Google Scholar
  4. Vinik AI (1992) Pancreatic islet cell regeneration and growth: introduction. Adv Exp Med Biol 321: 1–5
    Google Scholar
  5. Swenne I (1983) Effect of aging on the regenerative capacity of the pancreatic _Β_-cells of the rat. Diabetes 32: 14–19
    Google Scholar
  6. Pictet R, Rutter WJ (1972) Development of the embryonic pancreas. In: Steiner DF, Freinkel N (eds) Handbook of physiology, sect 7. Endocrinology, vol 1. American Physiological Society, Washington, pp 25–66
    Google Scholar
  7. Fuji S (1979) Development of pancreatic endocrine cell in the rat fetus. Arch Histol Jpn 42: 467–479
    PubMed Google Scholar
  8. Rutter WJ (1980) The development of the endocrine and exocrine pancreas. In: Fitzgerald PJ, Morrison AB (eds) The pancreas: Williams and Wilkins, Baltimore, pp 30–38
    Google Scholar
  9. Swenne I (1982) The role of glucose in the vitro regulation of cell cycle kinetics and proliferation of fetal pancreatic _Β_-cells. Diabetes 31: 745–760
    Google Scholar
  10. Hellerström C, Swenne I (1991) Functional maturation and proliferation of fetal pancreatic _Β_-cells. Diabetes 40 [Suppl 2]: 89–93
    PubMed Google Scholar
  11. Githens S (1993) Differentiation and development of the pancreas in animals. In: Go Vay Liang W, Lebenthal E, Di-Magno EP, Gardner JD, Reber HA, Scheele GA (eds) The pancreas: biology, and disease. Raven Press, New York, pp 21–55
    Google Scholar
  12. Wang RN, Bouwens L, Klöppel G (1994) Beta cell proliferation in normal and streptozotocin-treated newborn rats: site, dynamics and capacity. Diabetologia 37: 1088–1096
    PubMed Google Scholar
  13. Bouwens L, Wang RN, De Blay E, Pipeleers DG, Klöppel G (1994) Cytokeratins as markers of ductal cell differentiation and islet neogenesis in the neonatal rat pancreas. Diabetes 43: 1279–1283
    PubMed Google Scholar
  14. Brockenbrough JS, Weir GC, Bonner-Weir S (1988) Discordance of exocrine and endocrine growth after 90% pancreatectomy in rats. Diabetes 37: 232–236
    PubMed Google Scholar
  15. Bonner-Weir S, Baxter LA, Schuppin GT, Smith F (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas: a possible recapitulation of embryonic development. Diabetes 42: 1715–1720
    PubMed Google Scholar
  16. Sarvetnick NE, Gu D (1992) Regeneration of pancreatic endocrine cells in interferon-gamma transgenic mice. Adv Exp Med Biol 321: 85–89
    PubMed Google Scholar
  17. Gu D, Sarvetnick N (1993) Epithelial cell proliferation and islet neogenesis in IFN-gamma transgenic mice. Development 118: 33–46
    PubMed Google Scholar
  18. Wang TC, Bonner-Weir S, Oates PS, Chulak MB, Simon B (1993) Pancreatic gastrin stimulates islet differentiation of transforming growth factor α-induced ductular precursor cells. J Clin Invest 92: 1349–1356
    PubMed Google Scholar
  19. Rosenberg L, Vinik AI (1989) Induction of endocrine cell differentiation: a new approach to management of diabetes. J Lab Clin Med 114: 75–83
    PubMed Google Scholar
  20. Rosenberg L, Vinik AI (1992) Trophic stimulation of the ductular-islet cell axis: a new approach to the treatment of diabetes. Adv Exp Med Biol 321: 95–104
    PubMed Google Scholar
  21. Dudek RW, Lawrence IR, Hill R Jr, Johnson R (1991) Induction of islet cytodifferentiation by fetal mesenchyme in adult pancreatic ductal epithelium. Diabetes 40: 1041–1048
    PubMed Google Scholar
  22. Hultquist GT, Jönsson LE (1965) Ligation of the pancreatic duct in rats. Acta Soc Med Upsal 70: 82–88
    PubMed Google Scholar
  23. Pipeleers DG, Schuit FC, In't Veld PA et al. (1985) Interplay of nutrients and hormones in the regulation of insulin release. Endocrinology 117: 824–833
    PubMed Google Scholar
  24. Weibel ER (1979) Stereological methods. In: Weibel ER (ed) Practical methods for biological morphometry, vol 1. Academic Press, London, pp 26–37
    Google Scholar
  25. Oberholzer M, Heitz PU, Klöppel G, Ehrsam RE (1984) Morphometry in endocrine pathology. Path Res Pract 179: 220–224
    PubMed Google Scholar
  26. Williams MA (1985) Stereological techniques. In: Williams MA (ed) Quantitative methods in biology. North-Holland, Amsterdam, pp 5–84
    Google Scholar
  27. Aherne WA, Camplejohn RS, Wright NA (1977) An introduction to cell population kinetics. Edward Arnold, London, pp 88
    Google Scholar
  28. Walker NI, Winterford CM, Kerr JFR (1992) Ultrastructure of the rat pancreas after experimental duct ligation. II. Duct and stromal cell proliferation, differentiation, and deletion. Pancreas 7: 420–434
    PubMed Google Scholar
  29. Yamaguchi Y, Matsuno K, Goto M, Ogawa M (1993) In situ kinetics of acinar, duct, and inflammatory cells in duct ligation-induced pancreatitis in rats. Gastroenterology 104: 1498–1506
    PubMed Google Scholar
  30. Edström C, Falkmer S (1967) Qualitative and quantitative morphology of rat pancreatic islet tissue five weeks after ligation of the pancreatic ducts. Acta Soc Med Upsal 72: 376–390
    PubMed Google Scholar
  31. Hultquist GT, Karlsson U, Hallner A Ch (1979) The regenerative capacity of the pancreas in duct-ligated rats. Exp Pathol 17: 44–52
    Google Scholar
  32. Isaksson G, Ihse I, Lundquist I (1983) Influence of pancreatic duct ligation on endocrine and exocrine rat pancreas. Acta Physiol Scand 117: 281–286
    PubMed Google Scholar
  33. Pang K, Mukonoweshuro C, Wong GG (1994) Beta cells arise from glucose transporter type 2 (Glut2)-expressing epithelial cells of the developing rat pancreas. Proc Natl Acad Sci 91: 9559–9563
    PubMed Google Scholar
  34. Walker NI (1987) Ultrastructure of the rat pancreas after experimental duct ligation. I. The role of apoptosis and intraepithelial macrophages in acinar cell deletion. Am J Pathol 126: 439–451
    PubMed Google Scholar
  35. Githens S (1988) The pancreatic duct cell: proliferative capabilities, specific characteristics, metaplasia, isolation, and culture. J Pediatric Gastr Nutr 7: 486–506
    Google Scholar
  36. Goto M, Matsuno K, Yamaguchi Y, Ezaki T, Ogawa M (1993) Proliferation kinetics of macrophage subpopulations in a rat experimental pancreatitis model. Arch Histol Cytol 56: 75–82
    PubMed Google Scholar

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Pathology, Free University of Brussels, Campus Jette, Laarbeeklaan 103, B-1090, Brussels, Belgium
    R. N. Wang, G. Klöppel & L. Bouwens

Authors

  1. R. N. Wang
    You can also search for this author inPubMed Google Scholar
  2. G. Klöppel
    You can also search for this author inPubMed Google Scholar
  3. L. Bouwens
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Wang, R.N., Klöppel, G. & Bouwens, L. Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats.Diabetologia 38, 1405–1411 (1995). https://doi.org/10.1007/BF00400600

Download citation

Key words