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The Altered Migration and Distribution of Systemically Administered Mesenchymal Stem Cells in Morphine-Treated Recipients

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Abstract

Mesenchymal stem cells (MSCs) have the ability to migrate to the site of injury or inflammation, and to contribute to the healing process. Since patients treated with MSCs are often users of analgesic drugs, to relieve their uncomfortable pain associated with the tissue disorder, there is a possibility of negative effects of these drugs on the migration of endogenous and exogenous MSCs. Therefore, we tested the impact of acute and chronic treatment with morphine on the migration and organ distribution of exogenous adipose tissue-derived MSCs in mouse models. Firstly, we showed that the incubation of MSCs with morphine significantly reduced the expression of adhesive molecules CD44 (HCAM), CD54 (ICAM-1) and CD106 (VCAM-1) on MSCs. Using a model of systemic administration of MSCs labeled with vital dye PKH26 and by the application of flow cytometry to detect living CD45−PKH26+ cells, we found a decreased number of labeled MSCs in the lung, spleen and bone marrow, and a significantly increased number of MSCs in the liver of morphine-treated recipients. A skin allograft model was used to study the effects of morphine on the migration of exogenous MSCs to the superficial wound. Intraperitoneally administered MSCs migrated preferentially to the wound site, and this migration was significantly decreased in the morphine-treated recipients. The present results showed that morphine significantly influences the distribution of exogenous MSCs in the body, and decreases their migration to the site of injury.

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References

  1. 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.

    Article  CAS  Google Scholar 

  2. Lan, Y., Kodati, S., Lee, H. S., Omoto, M., Jin, Y., & Chauhan, S. K. (2012). Kinetics and function of mesenchymal stem cells in corneal injury. Investigative Ophthalmology and Visual Sciences, 53, 3638–3644.

    Article  CAS  Google Scholar 

  3. Javorkova, E., Trosan, P., Zajicova, A., Krulova, M., Hajkova, M., & Holan, V. (2014). Modulation of the early inflammatory microenvironment in the alkali-burned eye by systemically administered interferon-γ-treated mesenchymal stromal cells. Stem Cells and Development, 23, 2490–2500.

    Article  CAS  Google Scholar 

  4. Assis, A. C., Carvalho, J. L., Jacoby, B. A., Ferreira, R. L., Castanheira, P., Diniz, S. O., Cardoso, V. N., Goes, A. M., & Ferreira, A. J. (2010). Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart. Cell Transplantation, 19, 219–230.

    Article  Google Scholar 

  5. Wu, Y., & Zhao, R. C. (2012). The role of chemokines in mesenchymal stem cell homing to myocardium. Stem Cell Reviews and Reports, 8, 243–250.

    Article  CAS  Google Scholar 

  6. Singh, A., Singh, A., & Sen, D. (2016). Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010–2015). Stem Cell Research and Therapy, 7(1), 82. https://doi.org/10.1186/s13287-016-0341-0.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cardenes, N., Aranda-Valderrama, P., Carney, J. P., Sellares Torres, J., Alvarez, D., Kocydirim, E., Wolfram Smith, J. A., Ting, A. E., Lagazzi, L., Yu, Z., Mason, S., Santos, E., Lopresti, B. J., & Rojas, M. (2019). Cell therapy for ARDS: efficacy of endobronchial versus intravenous administration and biodistribution of MAPCs in a large animal model. BMJ Open Respiratory Research. https://doi.org/10.1136/bmjresp-2018-000308.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hajkova, M., Jaburek, F., Porubska, B., Bohacova, P., Holan, V., & Krulova, M. (2019). Cyclosporine A promotes the therapeutic effect of mesenchymal stem cells on transplantation reaction. Clinical Science (London), 133, 2143–2157.

    Article  CAS  Google Scholar 

  9. Eggenhofer, E., Benseler, V., Kroemer, A., Popp, F. C., Geissler, E. K., Schlitt, H. J., Baan, C. C., Dahlke, M. H., & Hoogduijn, M. J. (2012). Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Frontiers in Immunology, 3, 297.

    Article  CAS  Google Scholar 

  10. Leibacher, J., & Henschler, R. (2016). Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Research and Therapy, 7, 7. https://doi.org/10.1186/s13287-015-0271-2.

  11. Ji, J. F., He, B. P., Dheen, S. T., & Tay, S. S. (2004). Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells, 22, 415–427.

    Article  CAS  Google Scholar 

  12. Chamberlain, G., Wright, K., Rot, A., Ashton, B., & Middleton, J. (2008). Murine mesenchymal stem cells exhibit a restricted repertoire of functional chemokine receptors: comparison with human. PLoS One, 3(8), e2934. https://doi.org/10.1371/journal.pone.0002934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rankin, S. M. (2012). Chemokines and adult bone marrow stem cells. Immunology Letters, 145, 47–54.

    Article  CAS  Google Scholar 

  14. Nitzsche, F., Müller, C., Lukomska, B., Jolkkonen, J., Deten, A., & Boltze, J. (2017). Concise Review: MSC adhesion cascade-insights into homing and transendothelial migration. Stem Cells, 35, 1446–1460.

    Article  Google Scholar 

  15. Abumaree, M., Al Jumah, M., Pace, R. A., & Kalionis, B. (2012). Immunosuppressive properties of mesenchymal stem cells. Stem Cell Reviews, 8, 375–392.

    Article  CAS  Google Scholar 

  16. English, K. (2013). Mechanisms of mesenchymal stromal cell immunomodulation. Immunology and Cell Biology, 91, 19–26.

    Article  CAS  Google Scholar 

  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, 12, 654–663.

    Article  CAS  Google Scholar 

  18. 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 and Alcohol Dependence, 156, 139–149.

    Article  Google Scholar 

  19. 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. (2017). Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. Gut. https://doi.org/10.1136/gutjnl-2017-313717.

    Article  PubMed  Google Scholar 

  20. Wang, Y., Gupta, M., Farooqui, M., Li, Y., Peng, F., Rao, S., Ansonoff, M., Pintar, J. E., & Gupta, K. (2017). Opioids and opioid receptors orchestrate wound repair. Translational Research, 185, 13–23.

    Article  CAS  Google Scholar 

  21. Holan, V., Cechova, K., Zajicova, A., Kossl, J., Hermankova, B., Bohacova, P., Hajkova, M., Krulova, M., Svoboda, P., & Javorkova, E. (2018). The impact of morphine on the characteristics and function properties of human mesenchymal stem cells. Stem Cell Reviews and Reports, 14, 801–811.

    Article  CAS  Google Scholar 

  22. Hajkova, M., Javorkova, E., Zajicova, A., Trosan, P., Holan, V., & Krulova, M. (2017). A local application of mesenchymal stem cells and cyclosporine A attenuates immune response by a switch in macrophage phenotype. Journal of Tissue Engineering and Regenerative. Medicine, 11, 1456–1465.

    Article  CAS  Google Scholar 

  23. Billingham, R. E., Brent, L., Medawar, P. B., & Sparrow, E. M. (1954). Quantitative studies on tissue transplantation immunity. I. The survival times of skin homografts exchanged between members of different inbred strains of mice. Proceedings of the Royal Society of London B: Biological Sciences, 143, 43–58.

    CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. Bortolotto, V., & Grilli, M. (2017). Opiate analgesics as negative modulators of adult hippocampal neurogenesis: Potential implications in clinical practice. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2017.00254.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lam, C. F., Chang, P. J., Huang, Y. S., et al. (2008). Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesthesia and Analgesia, 107, 686–692.

    Article  CAS  Google Scholar 

  27. Zhang, J., Huang, X., Wang, H., Liu, X., Zhang, T., Wang, Y., & Hu, D. (2015). The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Research and Therapy, 6, 234.

    Article  Google Scholar 

  28. Shim, G., Lee, S., Han, J., Kim, G., Jin, H., Miao, W., Yi, T. G., Cho, Y. K., Song, S. U., & Oh, Y. K. (2015). Pharmacokinetics and in vivo fate of intra-articularly transplanted human bone marrow-derived clonal mesenchymal stem cells. Stem Cells and Development, 24, 1124–1132.

    Article  CAS  Google Scholar 

  29. Herrera, M. B., Bussolati, B., Bruno, S., Morando, L., Mauriello-Romanazzi, G., Sanavio, F., Stamenkovic, I., Biancone, L., & Camussi, G. (2007). Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney International, 72, 430–441.

    Article  CAS  Google Scholar 

  30. Wagner, W., Ho, A. D., & Zenke, M. (2010). Different facets of aging in human mesenchymal stem cells. Tissue Engineering Part B Reviews, 16, 445–453.

    Article  Google Scholar 

  31. Rombouts, W. J., & Ploemacher, R. E. (2003). Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia, 17, 160–170.

    Article  CAS  Google Scholar 

  32. Liu, X. B., Chen, H., Chen, H. Q., Zhu, M. F., Hu, X. Y., Wang, Y. P., Jiang, Z., Xu, Y. C., Xiang, M. X., & Wang, J. A. (2012). Angiopoietin-1 preconditioning enhances survival and functional recovery of mesenchymal stem cell transplantation. Journal of Zhejiang University - Science B, 13, 616–623.

    Article  CAS  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. 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.

    Article  Google Scholar 

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Funding

This work was supported by the project No. LTAUSA18110 – Inter-Excellence from the Ministry of Education, Youth and Sports of the Czech Republic, grant No. 19-02290S from the Grant Agency of the Czech Republic, project RVO:6798523 from the Institute of Physiology and by the Charles University programs SVV 260435 and 20604315 PROGRES Q43.

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Authors and Affiliations

  1. Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20, Prague 4, Czech Republic

    Vladimir Holan, Barbora Echalar, Katerina Palacka, Jan Kossl, Pavla Bohacova, Magdalena Krulova & Alena Zajicova

  2. Department of Cell Biology, Faculty of Science, Charles University, 128 43, Prague 2, Czech Republic

    Vladimir Holan, Barbora Echalar, Katerina Palacka, Jan Kossl, Pavla Bohacova & Magdalena Krulova

  3. Department of Biomathematics, Institute of Physiology of the Czech Academy of Sciences, 142 20, Prague 4, Czech Republic

    Jana Brejchova & Petr Svoboda

Authors
  1. Vladimir Holan
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  2. Barbora Echalar
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  9. Alena Zajicova
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Contributions

All authors contributed to this study. VH and PS designed the study, VH, BE, KP, AZ, JK, PB and JB performed the experiments, VH and PS wrote the paper, all authors read and approved the final manuscript.

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Correspondence to Vladimir Holan.

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Human and Animal Rights

This study did not involve human participants. The experiments with animals were approved by the local Animal Ethics Committee of the Institute of Experimental Medicine of the Czech Academy of Sciences, Prague.

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The authors declare that they have no conflict of interest.

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Holan, V., Echalar, B., Palacka, K. et al. The Altered Migration and Distribution of Systemically Administered Mesenchymal Stem Cells in Morphine-Treated Recipients. Stem Cell Rev and Rep 17, 1420–1428 (2021). https://doi.org/10.1007/s12015-021-10126-w

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