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Stem Cell Reviews and Reports

, Volume 14, Issue 6, pp 801–811 | Cite as

The Impact of Morphine on the Characteristics and Function Properties of Human Mesenchymal Stem Cells

  • Vladimir HolanEmail author
  • Kristina Cechova
  • Alena Zajicova
  • Jan Kossl
  • Barbora Hermankova
  • Pavla Bohacova
  • Michaela Hajkova
  • Magdalena Krulova
  • Petr Svoboda
  • Eliska Javorkova
Article
  • 232 Downloads

Abstract

Morphine is an analgesic drug therapeutically administered to relieve pain. However, this drug has numerous side effects, which include impaired healing and regeneration after injuries or tissue damages. It suggests negative effects of morphine on stem cells which are responsible for tissue regeneration. Therefore, we studied the impact of morphine on the properties and functional characteristics of human bone marrow-derived mesenchymal stem cells (MSCs). The presence of μ-, δ- and κ-opioid receptors (OR) in untreated MSCs, and the enhanced expression of OR in MSCs pretreated with proinflammatory cytokines, was demonstrated using immunoblotting and by flow cytometry. Morphine modified in a dose-dependent manner the MSC phenotype, inhibited MSC proliferation and altered the ability of MSCs to differentiate into adipocytes or osteoblasts. Furthermore, morphine rather enhanced the expression of genes for various immunoregulatory molecules in activated MSCs, but significantly inhibited the production of the vascular endothelial growth factor, hepatocyte growth factor or leukemia inhibitory factor. All of these observations are underlying the selective impact of morphine on stem cells, and offer an explanation for the mechanisms of the negative effects of opioid drugs on stem cells and regenerative processes after morphine administration or in opioid addicts.

Keywords

Mesenchymal stem cells Morphine Opioid receptors Gene expression Growth factors Cytokines 

Notes

Acknowledgements

This work was supported by grants from the Grant Agency of the Czech Republic no. 17-07070S and 17-05903S, the projects LO1309 and LO1508 from the Ministry of Education, Youth and Sports of the Czech Republic, institutional support of the Institute of Physiology (RVO:6798523) and by the project SVV 244-260435 from Charles University, Prague.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Barlass, U., Dutta, R., Cheema, H., George, J., Sareen, A., Dixit, A., Yuan, Z., Giri, B., Meng, J., Banerjee, S., Banerjee, S., Dudeja, V., Dawra, R. K., Roy, S., & Saluja, A. K. (2018). Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. Gut, 67, 600–602.PubMedGoogle Scholar
  2. 2.
    Bayer, R., Franke, H., Ficker, C., Richter, M., Lessig, R., Büttner, A., & Weber, M. (2015). Alterations of neuronal precursor cells in stages of human adult neurogenesis in heroin addicts. Drug Alcohol Dependence, 156, 139–149.CrossRefGoogle Scholar
  3. 3.
    Abdyazdani, N., Nourazarian, A., Nozad Charoudeh, H., Kazemi, M., Feizy, N., Akbarzade, M., Mehdizadeh, A., Rezaie, J., & Rahbarghazi, R. (2017). The role of morphine on rat neural stem cells viability, neuro-angiogenesis and neuro-steroidgenesis properties. Neuroscience Letters, 636, 205–212.CrossRefGoogle Scholar
  4. 4.
    Feizy, N., Nourazarian, A., Rahbarghazi, R., Nozad Charoudeh, H., Abdyazdani, N., Montazersaheb, S., & Narimani, M. (2016). Morphine inhibited the rat neural stem cell proliferation rate by increasing neuro steroid genesis. Neurochemical Research, 41, 1410–1419.CrossRefGoogle Scholar
  5. 5.
    Willner, D., Cohen-Yeshurun, A., Avidan, A., Ozersky, V., Shohami, E., & Leker, R. R. (2014). Short term morphine exposure in vitro alters proliferation and differentiation of neural progenitor cells and promotes apoptosis via mu receptors. PLoS One, 9(7), e103043.  https://doi.org/10.1371/journal.pone.0103043.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lam, C. F., Chang, P. J., Huang, Y. S., Sung, Y. H., Huang, C. C., Lin, M. W., Liu, Y. C., & Tsai, Y. C. (2008). Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesthesia and Analgesia, 107, 686–692.CrossRefGoogle Scholar
  7. 7.
    Rook, J. M., & McCarson, K. E. (2007). Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release. Biochemical Pharmacology, 74, 752–757.CrossRefGoogle Scholar
  8. 8.
    Rook, J. M., Hasan, W., & McCarson, K. E. (2009). Morphine-induced early delays in wound closure: involvement of sensory neuropeptides and modification of neurokinin receptor expression. Biochemical Pharmacology, 77, 1747–1755.CrossRefGoogle Scholar
  9. 9.
    Chrastil, J., Sampson, C., Jones, K. B., & Higgins, T. F. (2013). Postoperative opioid administration inhibits bone healing in an animal model. Clinical Orthopaedics and Related Research, 471, 4076–4081.CrossRefGoogle Scholar
  10. 10.
    Dominici, M., Le Blanc, K., Mueller, I., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–327.CrossRefGoogle Scholar
  11. 11.
    Holan, V., Trosan, P., Cejka, C., Javorkova, E., Zajicova, A., Hermankova, B., Chudickova, M., & Cejkova, J. (2015). A comparative study of the therapeutic potential of mesenchymal stem cells and limbal epithelial stem cells for ocular surface reconstruction. Stem Cells Translational Medicine, 4, 1052–1063.CrossRefGoogle Scholar
  12. 12.
    Le Blanc, K. (2006). Mesenchymal stromal cells: Tissue repair and immune modulation. Cytotherapy, 8, 559–561.CrossRefGoogle Scholar
  13. 13.
    Sasaki, M., Abe, R., Fujita, Y., Ando, S., Inokuma, D., & Shimizu, H. (2008). Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. Journal of Immunology, 180, 2581–2587.CrossRefGoogle Scholar
  14. 14.
    Squillaro, T., Peluso, G., & Galderisi, U. (2016). Clinical trials with mesenchymal stem cells: An update. Cell Transplantation, 25, 829–848.CrossRefGoogle Scholar
  15. 15.
    Abumaree, M., Al Jumah, M., Pace, R. A., & Kalionis, B. (2012). Immunosuppressive properties of mesenchymal stem cells. Stem Cell Reviews, 8, 375–392.CrossRefGoogle Scholar
  16. 16.
    English, K. (2013). Mechanisms of mesenchymal stromal cell immunomodulation. Immunology and Cell Biology, 91, 19–26.CrossRefGoogle Scholar
  17. 17.
    Holan, V., Hermankova, B., Bohacova, P., Kossl, J., Chudickova, M., Hajkova, M., Krulova, M., Zajicova, A., & Javorkova, E. (2016). Distinct immunoregulatory mechanisms in mesenchymal stem cells: Role of the cytokine environment. Stem Cell Reviews and Reports, 12, 654–663.CrossRefGoogle Scholar
  18. 18.
    Dholakiya, S. L., Aliberti, A., & Barile, F. A. (2016). Morphine sulfate concomitantly decreases neuronal differentiation and opioid receptor expression in mouse embryonic stem cells. Toxicology Letters, 247, 45–55.CrossRefGoogle Scholar
  19. 19.
    Hahn, J. W., Jagwani, S., Kim, E., Rendell, V. R., He, J., Ezerskiy, L. A., Wesselschmidt, R., Coscia, C. J., & Belcheva, M. M. (2010). Mu and kappa opioids modulate mouse embryonic stem cell-derived neural progenitor differentiation via MAP kinases. Journal of Neurochemistry, 112, 1431–1441.CrossRefGoogle Scholar
  20. 20.
    Higuchi, S., Ii, M., Zhu, P., & Ashraf, M. (2012). Delta-opioid receptor activation promotes mesenchymal stem cell survival via PKC/STAT3 signaling pathway. Circulation Journal, 76, 204–212.CrossRefGoogle Scholar
  21. 21.
    Ujcikova, H., Hlouskova, M., Cechova, K., Stolarova, K., Roubalova, L., & Svoboda, P. (2017). Determination of μ-, δ- and κ-opioid receptors in forebrain cortex of rats exposed to morphine for 10 days: Comparison with animals after 20 days of morphine withdrawal. PLoS One, 12(10), e0186797.  https://doi.org/10.1371/journal.pone.0186797.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cechova, K., Hlouskova, M., Javorkova, E., Roubalova, L., Ujcikova, H., Holan, V., & Svoboda, P. (2018). Up-regulation of μ-, δ- and κ-opioid receptors in concanavalin A-stimulated rat spleen lymphocytes. Journal of Neuroimmunology, 321, 12–23.CrossRefGoogle Scholar
  23. 23.
    Holan, V., Zajicova, A., Krulova, M., Blahoutova, V. &, Wilczek, H. (2003). Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clinical and Experimental Immunology, 132, 40–45.CrossRefGoogle Scholar
  24. 24.
    Plein, L. M., & Rittner, H. L. (2017). Opioids and the immune system - friend or foe. British Journal of Pharmacology, 175, 2717–2725.CrossRefGoogle Scholar
  25. 25.
    Tu, T., Zhang, C., Yan, H., Luo, Y., Kong, R., Wen, P., Ye, Z., Chen, J., Feng, J., Liu, F., Wu, J. Y., & Yan, X. (2015). CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development. Cell Research, 25, 275–287.CrossRefGoogle Scholar
  26. 26.
    Yan, H., Zhang, C., Wang, Z., Tu, T., Duan, H., Luo, Y., Feng, J., Liu, F., & Yan, X. (2017). CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis. Scientific Reports, 7(1), 7442.  https://doi.org/10.1038/s41598-017-06637-7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Chiossone, L., Conte, R., Spaggiari, G. M., Serra, M., Romei, C., Bellora, F., Becchetti, F., Andaloro, A., Moretta, L., & Bottino, C. (2016). Mesenchymal stromal cells induce peculiar alternatively activated macrophages capable of dampening both innate and adaptive immune responses. Stem Cells, 34, 1909–1921.CrossRefGoogle Scholar
  28. 28.
    Ferrara, N., & Gerber, H. P. (2002). The role of vascular endothelial growth factor in angiogenesis. Acta Haematological, 106, 148–156.CrossRefGoogle Scholar
  29. 29.
    Hofer, H. R., & Tuan, R. S. (2016). Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Research and Therapy, 7, 131.  https://doi.org/10.1186/s13287-016-0394-0.CrossRefPubMedGoogle Scholar
  30. 30.
    Nicola, N. A., & Babon, J. J. (2015). Leukemia inhibitory factor (LIF). Cytokine Growth Factor Reviews, 26, 533–544.CrossRefGoogle Scholar
  31. 31.
    Yue, X., Wu, L. & Hu, W. (2015). The regulation of leukemia inhibitory factor. Cancer Cell Microenvironment, 2(3). Pii: e877.Google Scholar
  32. 32.
    Conway, K., Price, P., Harding, K. G., & Jiang, W. G. (2006). The molecular and clinical impact of hepatocyte growth factor, its receptor, activators, and inhibitors in wound healing. Wound Repair and Regeneration, 14, 2–10.CrossRefGoogle Scholar
  33. 33.
    Bortolotto, V., & Grilli, M. (2017). Opiate analgesics as negative modulators of adult hippocampal neurogenesis: Potential implications in clinical practice. Frontiers in Pharmacology, 8.  https://doi.org/10.3389/fphar.2017.00254.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Vladimir Holan
    • 1
    • 2
    Email author
  • Kristina Cechova
    • 3
    • 4
  • Alena Zajicova
    • 1
  • Jan Kossl
    • 1
    • 2
  • Barbora Hermankova
    • 1
    • 2
  • Pavla Bohacova
    • 1
    • 2
  • Michaela Hajkova
    • 1
    • 2
  • Magdalena Krulova
    • 1
    • 2
  • Petr Svoboda
    • 3
  • Eliska Javorkova
    • 1
    • 2
  1. 1.Department of Transplantation ImmunologyInstitute of Experimental Medicine of the Czech Academy of SciencesPragueCzech Republic
  2. 2.Department of Cell Biology, Faculty of ScienceCharles UniversityPrague 2Czech Republic
  3. 3.Department of BiomathematicsInstitute of Physiology of the Czech Academy of SciencesPragueCzech Republic
  4. 4.Department of Biochemistry, Faculty of ScienceCharles UniversityPrague 2Czech Republic

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