Stem Cell Reviews and Reports

, Volume 7, Issue 1, pp 53–63 | Cite as

Vitamin D and Vitamin A Receptor Expression and the Proliferative Effects of Ligand Activation of These Receptors on the Development of Pancreatic Progenitor Cells Derived from Human Fetal Pancreas

  • Ka Yan Ng
  • Man Ting Ma
  • Kwan Keung Leung
  • Po Sing Leung
Article

Abstract

The growth and development of pancreatic islet cells are regulated by various morphogens. Vitamin A modulates in vitro differentiation of islet cells and vitamin D affects beta-cell insulin secretion, while both vitamin ligands act through heterodimerization with the retinoid X receptor (RXR). However, their effects in modulating pancreatic development have not been determined. In this study, cultured human pancreatic progenitor cells (PPCs) isolated from human fetal pancreas were stimulated to differentiate into islet-like cell clusters (ICCs). RT-PCR, Western blotting and immunocytochemistry were used to examine the expression and localization of vitamin D receptor (VDR), retinoic acid receptor (RAR), and RXR in PPCs. The effects of added all-trans retinoic acid (atRA, a form of vitamin A), calcitriol (activated vitamin D) and of these ligands together on PPC cell viability, proliferation and apoptosis were assessed by MTT, BrdU and ELISA assays, respectively. Post-treatment neurogenin-3 (NGN3) expression, necessary for islet-cell lineage development, was examined by real-time RT-PCR. Results showed that RAR, RXR and VDR were expressed in PPCs. RAR and RXR were localized in nuclei, and the VDR in nuclei, cytoplasm and plasma membrane. atRA and calcitriol each increased PPC viability and proliferation; atRA additionally decreased PPC apoptosis. Co-addition of atRA and calcitriol had no additive effects on cell viability but did increase ngn3 responses. In conclusion, RAR, RXR and VDR are expressed in human fetal PPCs and PPC proliferation can be promoted by calcitriol, atRA or both together, data valuable for elucidating mechanisms underlying islet development and for developing clinical islet transplantation.

Keywords

atRA Calcitriol Development Pancreas Progenitor cells RAR RXR Vitamin A Vitamin D VDR 

Notes

Acknowledgments

This work was fully supported by the General Research Grant from the Research Grants Council of Hong Kong (Project Ref. No.: CUHK 470709) and by the Focused Investment Scheme C from the Chinese University of Hong Kong (Ref. No.: 1903016), awarded to PS Leung. The authors would also like to thank BJ Boucher who critically reviewed this manuscript.

Conflict of Interest

The authors declare no potential conflicts of interest.

References

  1. 1.
    Kitabchi, A. E., Umpierrez, G. E., Miles, J. M., & Fisher, J. N. (2009). Hyperglycemic crises in adult patients with diabetes. Diabetes Care, 32, 1335–1343.CrossRefPubMedGoogle Scholar
  2. 2.
    Ovalle, F., Vaughan, T. B., Sohn, J. E., & Gower, B. (2008). Catamenial diabetic ketoacidosis and catamenial hyperglycemia: case report and review of the literature. American Journal of the Medical Sciences, 335, 298–303.CrossRefPubMedGoogle Scholar
  3. 3.
    Simó, R., & Hernández, C. (2009). Advances in the medical treatment of diabetic retinopathy. Diabetes Care, 32, 1556–1562.CrossRefPubMedGoogle Scholar
  4. 4.
    Marshall, S. M., & Flyvbjerg, A. (2006). Prevention and early detection of vascular complications of diabetes. British Medical Journal, 333, 475–480.CrossRefPubMedGoogle Scholar
  5. 5.
    Renner, R. (1990). Insulin injection therapy of diabetes mellitus. Fortschritte der Medizin, 108, 663–667.PubMedGoogle Scholar
  6. 6.
    Girish, C., Manikandan, S., & Jayanthi, M. (2006). Newer insulin analogues and inhaled insulin. Indian Journal of Medical Sciences, 60, 117–123.CrossRefPubMedGoogle Scholar
  7. 7.
    Lerner, S. M. (2008). Kidney and pancreas transplantation in type 1 diabetes mellitus. Mount Sinai Journal of Medicine, 75, 372–384.CrossRefPubMedGoogle Scholar
  8. 8.
    Kodama, S., & Faustman, D. L. (2004). Routes to regenerating islet cells: stem cells and other biological therapies for type 1 diabetes. Pediatric Diabetes, 2, 38–44.CrossRefGoogle Scholar
  9. 9.
    Evans-Molina, C., Vestermark, G. L., & Mirmira, R. G. (2009). Development of insulin-producing cells from primitive biologic precursors. Current Opinion in Organ Transplantation, 14, 56–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Suen, P. M., Chan, J. C., Lau, T. K., Yao, K. M., & Leung, P. S. (2008). PDZ-domain containing-2 (PDZD2) is a novel factor that affects the growth and differentiation of human fetal pancreatic progenitor cells. International Journal of Biochemistry and Cell Biology, 40, 789–803.CrossRefPubMedGoogle Scholar
  11. 11.
    Leung, K. K., Suen, P. M., Lau, T. K., Ko, W. H., Yao, K. M., & Leung, P. S. (2009). PDZ-domain containing-2 (PDZD2) drives the maturity of human fetal pancreatic progenitor-derived islet-like cell clusters with functional responsiveness against membrane depolarization. Stem Cells and Development, 18, 979–989.CrossRefPubMedGoogle Scholar
  12. 12.
    Niederreither, K., & Dollé, P. (2008). Retinoic acid in development: towards an integrated view. Nature Reviews, Genetics, 9, 541–553.CrossRefGoogle Scholar
  13. 13.
    Cheung, A. M., Tam, C. K., Chow, H. C., Verfaillie, C. M., Liang, R., & Leung, A. Y. (2007). All-trans retinoic acid induces proliferation of an irradiated stem cell supporting stromal cell line AFT024. Experimental Hematology, 35, 56–63.CrossRefPubMedGoogle Scholar
  14. 14.
    Wohl, C. A., & Weiss, S. (1998). Retinoic acid enhances neuronal proliferation and astroglial differentiation in cultures of CNS stem cell-derived precursors. Journal of Neurobiology, 37, 281–290.CrossRefPubMedGoogle Scholar
  15. 15.
    Oström, M., Loffler, K. A., Edfalk, S., et al. (2008). Retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into beta-cells. PLoS ONE, 3, e2841.CrossRefPubMedGoogle Scholar
  16. 16.
    Stafford, D., White, R. J., Kinkel, M. D., Linville, A., Schilling, T. F., Prince, V. E. (2006). Retinoids signal directly to zebra fish endoderm to specify insulin-expressing beta-cells. Development (Cambridge, England), 133, 5001.Google Scholar
  17. 17.
    Alexa, K., Choe, S. K., Hirsch, N., Etheridge, L., Laver, E., & Sagerström, C. G. (2009). Maternal and zygotic aldh1a2 activity is required for pancreas development in zebra fish. PLoS ONE, 4, e8261.CrossRefPubMedGoogle Scholar
  18. 18.
    Shi, Y., Hou, L., Tang, F., et al. (2005). Inducing embryonic stem cells to differentiate into pancreatic beta cells by a novel three-step approach with activin A and all-trans retinoic acid. Stem Cells, 23, 656–662.CrossRefPubMedGoogle Scholar
  19. 19.
    Feldman, D., Pike, J. W., & Glorieux, F. H. (2005). Vitamin D. UK: Elsevier, Academic.Google Scholar
  20. 20.
    Carlberg, C., & Seuter, S. (2007). The vitamin D receptor. Dermatologic Clinics, 4, 515–523.CrossRefGoogle Scholar
  21. 21.
    Kochupillai, N. (2008). The physiology of vitamin D: current concepts. Indian Journal of Medical Research, 127, 256–262.PubMedGoogle Scholar
  22. 22.
    Lee, S., Clark, S. A., Gill, R. K., & Christakos, S. (1994). 1, 25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion. Endocrinology, 134(4), 1601A–1601C.CrossRefGoogle Scholar
  23. 23.
    Norman, A. W., Frankel, J. B., Heldt, A. M., & Grodsky, G. M. (1980). Vitamin D deficiency inhibits pancreatic secretion of insulin. Science, 209, 823–825.CrossRefPubMedGoogle Scholar
  24. 24.
    Tanaka, Y., Seino, Y., Ishida, M., et al. (1984). Effect of vitamin D3 on the pancreatic secretion of insulin and somatostatin. Acta Endocrinologia, 105, 528–533.Google Scholar
  25. 25.
    Nyomba, B. L., Bouillon, R., & De Moor, P. (1984). Influence of vitamin D status on insulin secretion and glucose tolerance in the rabbit. Endocrinology, 115, 191–197.CrossRefPubMedGoogle Scholar
  26. 26.
    Bourlon, P.-M., Billaudel, B., & Faure-Dussert, A. (1999). Influence of vitamin D3 deficiency and 1, 25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat endocrine pancreas. Journal of Endocrinology, 160, 87–95.CrossRefPubMedGoogle Scholar
  27. 27.
    Cade, C., & Norman, A. W. (1987). Rapid normalization/stimulation by 1, 25-dihydrooxyvitamin D3 of insulin secretion and glucose tolerance in the vitamin D-deficient rat. Endocrinology, 120, 1490–1497.CrossRefPubMedGoogle Scholar
  28. 28.
    Alon, D. B., Chaimovitz, C., Dvilansky, A., et al. (2002). Novel role of 1, 25(OH)(2)D(3) in induction of erythroid progenitor cell proliferation. Experimental Hematology, 30, 403–409.CrossRefPubMedGoogle Scholar
  29. 29.
    Cianferotti, L., Cox, M., Skorija, K., & Demay, M. B. (2007). Vitamin D receptor is essential for normal keratinocyte stem cell function. Proceedings of the National of the Academic of Sciences of the United States of America, 104, 9428–9433.CrossRefGoogle Scholar
  30. 30.
    Saunders, D. E., Christensen, C., Williams, J. R., et al. (1995). Inhibition of breast and ovarian carcinoma cell growth by1, 25-dihydroxyvitamin D3 combined with retinoic acid or dexamethasone. Anti-Cancer Drugs, 6, 562–569.CrossRefPubMedGoogle Scholar
  31. 31.
    Brown, G., Bunce, C. M., Rowlands, D. C., & Williams, G. R. (1994). All trans retinoic acid and 1alpha, 25-dihydroxyvitamin D3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes. Leukemia, 8, 806–815.PubMedGoogle Scholar
  32. 32.
    Popadic, S., Ramic, Z., Medenica, L., et al. (2008). Antiproliferative effect of vitamin A and D analogues on adult human keratinocytes in vitro. Skin Pharmacology and Physiology, 21, 227–234.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang, Q., Yang, W., Uytingco, M. S., Christakos, S., & Wieder, R. (2000). 1, 25-Dihydroxyvitamin D3 and all-trans-retinoic acid sensitize breast cancer cells to chemotherapy-induced cell death. Cancer Research, 60, 2040–2048.PubMedGoogle Scholar
  34. 34.
    De Vos, S., Dawson, M. I., Holden, S., et al. (1997). Effects of retinoid X receptor-selective ligands on proliferation of prostate cancer cells. The Prostate, 32, 115–121.CrossRefPubMedGoogle Scholar
  35. 35.
    Lou, Y. R., Miettinen, S., Kagechika, H., Gronemeyer, H., & Tuohimaa, P. (2005). Retinoic acid via RARalpha inhibits the expression of 24-hydroxylase in human prostate stromal cells. Biochemical and Biophysical Research Communications, 338, 1973–1981.CrossRefPubMedGoogle Scholar
  36. 36.
    Salle, B. L., Delvin, E. E., Lapillonne, A., Bishop, N. J., & Glorieux, F. H. (2000). Perinatal metabolism of vitamin D. American Journal of Clinical Nutrition, 71(5 Suppl), 1317S–1324S.PubMedGoogle Scholar
  37. 37.
    Chomienne, C., Balitrand, N., Ballerini, P., Castaigne, S., de Thé, H., & Degos, L. (1991). All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells. Journal of Clinical Investigation, 88, 2150–2154.CrossRefPubMedGoogle Scholar
  38. 38.
    Wuarin, L., Chang, B., Wada, R., & Sidell, N. (1994). Retinoic acid up-regulates nuclear retinoic acid receptor-alpha expression in human neuroblastoma cells. International Journal of Cancer, 56, 840–845.CrossRefGoogle Scholar
  39. 39.
    Friedman, A., Halevy, O., Schrift, M., Arazi, Y., & Sklan, D. (1993). Retinoic acid promotes proliferation and induces expression of retinoic acid receptor-alpha gene in murine T lymphocytes. Cellular Immunology, 152, 240–248.CrossRefPubMedGoogle Scholar
  40. 40.
    Albrechtsson, E., Jonsson, T., Möller, S., Höglund, M., Ohlsson, B., & Axelson, J. (2003). Vitamin D receptor is expressed in pancreatic cancer cells and a vitamin D3 analogue decreases cell number. Pancreatology, 3, 41–46.CrossRefPubMedGoogle Scholar
  41. 41.
    Jensen, S. S., Madsen, M. W., Lukas, J., Bartek, J., & Binderup, L. (2002). Sensitivity to growth suppression by 1alpha, 25-dihydroxyvitamin D(3) among MCF-7 clones correlates with Vitamin D receptor protein induction. Journal of Steroid Biochemistry and Molecular Biology, 81, 123–133.CrossRefPubMedGoogle Scholar
  42. 42.
    Wiese, R. J., Uhland-Smith, A., Ross, T. K., Prahl, J. M., & DeLuca, H. F. (1992). Up-regulation of the vitamin D receptor in response to 1, 25-dihydroxyvitamin D3 results from ligand-induced stabilization. Journal of Biological Chemistry, 267, 20082–20086.PubMedGoogle Scholar
  43. 43.
    Li, X. Y., Boudjelal, M., Xiao, J. H., et al. (1999). 1, 25-Dihydroxyvitamin D3 increases nuclear vitamin D3 receptors by blocking ubiquitin/proteasome-mediated degradation in human skin. Molecular Endocrinology, 13, 1686–1694.CrossRefPubMedGoogle Scholar
  44. 44.
    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 National Academic of Sciences of the United States of America, 97, 1607–1611.CrossRefGoogle Scholar
  45. 45.
    Masterjohn, C. (2009). The cod liver oil debate: Science validates the benefits of our number one superfood (pp. 18–25). Spring: Wise Transitions.Google Scholar
  46. 46.
    Morgan, A. F., Kimmel, L., & Hawkins, N. C. (1937). A comparison of the hypervitaminoses induced by irradiated ergosterol and fish liver oil concentrates. Journal of Biological Chemistry, 120, 85–102.Google Scholar
  47. 47.
    Metz, A. L., Walser, M. M., & Olson, W. G. (1985). The interaction of dietary vitamin A and vitamin D related to skeletal development in the turkey poult. Journal of Nutrition, 115, 929–935.PubMedGoogle Scholar
  48. 48.
    Clerk, I., & Bassett, C. A. L. (1962). The amelioration of hypervitaminosis D in rats with vitamin A. Journal of Experimental Medicine, 115, 147–156.CrossRefGoogle Scholar
  49. 49.
    Clerk, I., & Smith, M. R. (1963). Effects of hypervitaminosis A and D on skeletal metabolism. Journal of Biological Chemistry, 239, 1266–1271.Google Scholar
  50. 50.
    Sarkar, S. A., Kobberup, S., Wong, R., et al. (2008). Global gene expression profiling and histochemical analysis of the developing human fetal pancreas. Diabetologia, 51, 285–297.CrossRefPubMedGoogle Scholar
  51. 51.
    Muindi, J. R., Nganga, A., Engler, K. L., Coignet, L. J., Johnson, C. S., & Trump, D. L. (2007). CYP24 splicing variants are associated with different patterns of constitutive and calcitriol-inducible CYP24 activity in human prostate cancer cell lines. Journal of Steroid Biochemistry and Molecular Biology, 103, 334–337.CrossRefPubMedGoogle Scholar
  52. 52.
    Lampen, A., Meyer, S., & Nau, H. (2001). Phytanic acid and docosahexaenoic acid increase the metabolism of all-trans-retinoic acid and CYP26 gene expression in intestinal cells. Biochimica et Biophysica Acta, 1521, 97–106.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ka Yan Ng
    • 1
  • Man Ting Ma
    • 1
  • Kwan Keung Leung
    • 1
  • Po Sing Leung
    • 1
  1. 1.School of Biomedical Sciences, Faculty of MedicineThe Chinese University of Hong KongHong KongChina

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