Negative impacts of nanomaterials on stem cells and cells of the immune system are one of the main causes of an impaired or slowed tissue healing. Therefore, we tested effects of four selected types of metal nanoparticles (NPs): zinc oxide (ZnO), copper oxide (CuO), silver (Ag), and titanium dioxide (TiO2) on the metabolic activity and secretory potential of mouse mesenchymal stem cells (MSCs), and on the ability of MSCs to stimulate production of cytokines and growth factors by macrophages. Individual types of nanoparticles differed in the ability to inhibit metabolic activity, and significantly decreased the production of cytokines and growth factors (interleukin-6, vascular endothelial growth factor, hepatocyte growth factor, insulin-like growth factor-1) by MSCs, with the strongest inhibitory effect of CuO NPs and the least effect of TiO2 NPs. The recent studies indicate that immunomodulatory and therapeutic effects of transplanted MSCs are mediated by macrophages engulfing apoptotic MSCs. We co-cultivated macrophages with heat-inactivated MSCs which were untreated or were preincubated with the highest nontoxic concentrations of metal NPs, and the secretory activity of macrophages was determined. Macrophages cultivated in the presence of both untreated MSCs or MSCs preincubated with NPs produced significantly enhanced and comparable levels of various cytokines and growth factors. These results suggest that metal nanoparticles inhibit therapeutic properties of MSCs by a direct negative effect on their secretory activity, but MSCs cultivated in the presence of metal NPs have preserved the ability to stimulate cytokine and growth factor production by macrophages.

Department of Cell Biology Faculty of Science Charles University 12843 Prague 2 Czech Republic

Department of Nanotoxicology and Molecular Epidemiology Institute of Experimental Medicine of the Czech Academy of Sciences 14220 Prague 4 Czech Republic

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Lewinski, N., Colvin, V., & Drezek, R. (2008). Cytotoxicity of nanoparticles. Small, 4, 26–49. PubMed DOI

Huang, Y. W., Cambre, M., & Lee, H. J. (2017). The toxicity of nanoparticles depends on multiple molecular and physicochemical mechanisms. International Journal of Molecular Sciences, 18, 2702. PubMed DOI PMC

Liu, X., Yang, Z., Sun, J., Ma, T., Hua, F., & Shen, Z. (2019). A brief review of cytotoxicity of nanoparticles on mesenchymal stem cells in regenerative medicine. International Journal of Nanomedicine, 14, 3875–3892. PubMed DOI PMC

Pandey, A., Malek, V., Prabhakar, V., Kulkarni, Y. A., & Gaikwad, A. B. (2015). Nanoparticles: A neurotoxicological perspective. CNS and Neurological Disorders - Drug Targets, 14, 1317–1327. PubMed DOI

Lu, X., Miousse, I. R., Pirela, S. V., Melnyk, S., Koturbash, I., & Demokritou, P. (2016). Short-term exposure to engineered nanomaterials affects cellular epigenome. Nanotoxicology, 10, 40–150.

Rossner, P., Jr, Vrbova, K., Strapacova, S., Rossnerova, A., Ambroz, A., Brzicova, T., et al. (2019). Inhalation of ZnO nanoparticles: splice junction expression and alternative splicing in mice. Toxicological Sciences, 168, 190–200. PubMed DOI

Petrarca, C., Clemente, E., Amato, V., Pedata, P., Sabbioni, E., & Bernardinic, G. (2015). etal. Engineered metal-based nanoparticles and innate immunity. Clinical and Molecular Allergy, 13. https://doi.org/10.1186/s12948-015-0020-1

Dobrovolskaia, M. A., Shurin, M., & Shvedova, A. A. (2016). Current understanding of interactions between nanoparticles and the immune system. Toxicology and Applied Pharmacology, 299, 78–89. PubMed DOI

Holan, V., Javorkova, E., Vrbova, K., Vecera, Z., Mikuska, P., Coufalik, P., et al. (2019). A murine model of the effects of inhaled CuO nanoparticles on cells of innate and adaptive immunity - a kinetic study of a continuous three-month exposure. Nanotoxicology, 13, 952–963. PubMed DOI

Rajanahalli, P., Stucke, C. J., & Hong, Y. (2015). The effects of silver nanoparticles on mouse embryonic stem cell self-renewal and proliferation. Toxicology Reports, 2, 758–764. PubMed DOI PMC

Senut, M., Zhang, C., Liu, Y., Sen, F., Ruden, A., & Mao, D. M. (2016). Size-dependent toxicity of gold nanoparticles on human embryonic stem cells and their neural derivatives. Small, 12, 631–646. PubMed DOI

Gao, X., Topping, V. D., Keltner, Z., Sprando, R. L., & Yourick, J. J. (2017). Toxicity of nano- and ionic silver to embryonic stem cells: a comparative toxicogenomic study. Journal of Nanobiotechnology, 15(1), 31. PubMed DOI PMC

Park, M. V., Annema, W., Salvati, A., Lesniak, A., Elsaesser, A., & Barnes, C. (2009). Vitro. Toxicology and Applied Pharmacology, 240, 108–116. PubMed DOI

Bregoli, L., Chiarini, F., Gambarelli, A., Sighinolfi, G., Gatti, A. M., Santi, P., et al. (2009). Toxicity of antimony trioxide nanoparticles on human hematopoietic progenitor cells and comparison to cell lines. Toxicology, 262, 121–129. PubMed DOI

Hou, Y., Cai, K., Li, J., Chen, X., Lai, M., Hu, Y., et al. (2013). Effects of titanium nanoparticles on adhesion, migration, proliferation, and differentiation of mesenchymal stem cells. International Journal of Nanomedicine, 8, 3619–3630.

Orazizadeh, M., Khodadadi, A., Bayati, V., Saremy, S., Farasat, M., & Khorsandi, L. (2015). In vitro toxic effects of zinc oxide nanoparticles on rat adipose tissue-derived mesenchymal stem cells. Cell Journal, 17, 412–421. PubMed PMC

Sengstock, C., Diendorf, J., Epple, M., Schildhauer, T. A., & Köller, M. (2014). Effect of silver nanoparticles on human mesenchymal stem cell differentiation. Beilstein Journal of Nanotechnology, 5, 2058–2069. PubMed DOI PMC

Lykov, A. P., Lykova, Y. A., Poveshchenko, O. V., Bondarenko, N. A., Surovtseva, M. A., & Bgatova, N. P. (2017). Toxic effects of nanostructured silicon dioxide on multipotent mesenchymal stromal cells. Bulletin of Experimental Biology and Medicine, 163, 159–162. PubMed DOI

Zhang, R., Lee, P., Lui, V. C., Chen, Y., Liu, X., Lok, C. N., et al. (2015). Silver nanoparticles promote osteogenesis of mesenchymal stem cells and improve bone fracture healing in osteogenesis mechanism mouse model. Nanomedicine: The Official Journal of the American Academy of Nanomedicine, 11, 1949–1959. DOI

Yi, C., Liu, D., Fong, C. C., Zhang, J., & Yang, M. (2010). Gold nanoparticles promote osteogenic differentiation of mesenchymal stem cells through p38 MAPK pathway. Acs Nano, 4, 6439–6448. PubMed DOI

Qin, H., Zhu, C., An, Z., Jiang, Y., Zhao, Y., & Wang, J. (2014). International Journal of Nanomedicine, 9, 2469–2478. PubMed DOI PMC

Zhang, X. F., Shen, W., & Gurunathan, S. (2016). Silver nanoparticle-mediated cellular responses in various cell lines: an in vitro model. International Journal of Molecular Sciences, 17(10), 1603. PubMed DOI PMC

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

Han, Y., Li, X., Zhang, Y., Han, Y., Chang, F., & Ding, J. (2019). Mesenchymal stem cells for regenerative medicine. Cells, 8(8), 886. PubMed DOI PMC

de Witte, S. F. H., Luk, F., Sierra Parraga, J. M., Merino, A., Korevaar, M. A., Shankar, A. S., et al. (2018). Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cells, 36, 602–615. PubMed DOI

Preda, M. B., Neculachi, C. A., Fenyo, I. M., Vacaru, A. M., Publik, M. A., & Simionescu, M. (2021). Short lifespan of syngeneic transplanted MSC is a consequence of in vivo apoptosis and immune cell recruitment in mice. Cell Death and Disease, 12, 566. PubMed DOI PMC

Brzicova, T., Javorkova, E., Vrbova, K., Zajicova, A., Holan, V., Pinkas, D., et al. (2019). Molecular responses in THP-1 macrophage-like cells exposed to diverse nanoparticles. Nanomaterials (Basel), 9(5), 687. PubMed DOI

Remzova, M., Zouzelka, R., Brzicova, T., Vrbova, K., Pinkas, D., Rossner, P., et al. (2019). Toxicity of TiO2, ZnO, and SiO2 nanoparticles in human lung cells: safe-by-design development of construction materials. Nanomaterials (Basel), 9(7), 687.

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 Engeneering and Regenerative Medicine, 11, 1456–1465.

Holan, V., Echalar, B., Palacka, K., Kossl, J., Bohacova, P., Krulova, M. et al. (2021). The altered migration and distribution of systemically administered mesenchymal stem cells in morphine-treated recipients. Stem Cell Reviews and Reports, 17, 1420–1428.

Holan, V., Cechova, K., Zajicova, A., Kossl, J., Hermankova, B., Bohacova, P., et al. (2018). The impact of morphine on the characteristics and function properties of human mesenchymal stem cells. Stem Cell Reviews and Reports, 14, 801–811. PubMed DOI

Bondarenko, O., Juganson, K., Ivask, A., Kasemets, K., Mortimer, M., & Kahru, A. (2013). Archives of Toxicology, 87, 1181–1200. PubMed DOI PMC

Solano, R., Patiño-Ruiz, D., Tejeda-Benitez, L., & Herrera, A. (2021). Metal- and metal/oxide-based engineered nanoparticles and nanostructures: a review on the applications, nanotoxicological effects, and risk control strategies. Environmental Sciences and Pollution Research, 28, 16962–16981. DOI

Li, H., Shen, S., Fu, H., Wang, Z., Lim, X., Sui, X., et al. (2019). Immunomodulatory functions of mesenchymal stem cells in tissue engineering. Stem Cells International, 19, 9671206.

Fan, X. L., Zhang, Y., Li, X., & Fu, Q. L. (2020). Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cellular and Molecular Life Sciences, 77, 2771–2794.

Karlsson, H., Cronholmm, P., Gustafsson, J., & Möller, L. (2008). Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes. Chemical Research in Toxicology, 21, 1726–1732. PubMed DOI

Moschini, E., Maurizio Gualtieri, M., Colombo, M., Fascio, U., Camatini, M., & Mantecca, P. (2013). The modality of cell-particle interactions drives the toxicity of nanosized CuO and TiO2 in human alveolar epithelial cells. Toxicology Letters, 222, 102–116. PubMed DOI

Tolliver, L. M., Holl, N. J., Hou, F. Y. S., Lee, H. J., Cambre, M. H., & Huang, Y. W. (2020). Differential cytotoxicity induced by transition metal oxide nanoparticles is a function of cell killing and suppression of cell proliferation. International Journal of Molecular Sciences, 21(5), 1731.

Dayem, A. A., Lee, S. B., & Cho, S. G. (2018). The impact of metallic nanoparticles on stem cell proliferation and differentiation. Nanomaterials (Basel), 8(10), 761. DOI

Han, Y., Yang, J., Fang, J., Zhou, Y., Candi, E., Wang, J., et al. (2022). The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduction and Targeted Therapy, 7(1), 92. DOI

Holan, V., Echalar, B., Palacka, K., Kossl, J., Bohacova, P., Porubska, B. et al. (2022). The inability of ex vivo expanded mesenchymal stem/stromal cells to survive in newborn mice and to induce transplantation tolerance. Stem Cell Reviews and Reports, 18(7), 2365–2375.

Eggenhofer, E., Benseler, V., Kroemer, A., Popp, F. C., Geissler, E. K., Schlitt, H. J., et al. (2012). Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Frontiers in Immunology, 3, 297. PubMed DOI PMC