Some metal nanoparticles (NP) are characterized by antimicrobial properties with the potential to be used as alternative antibiotics. However, NP may negatively impact human organism, including mesenchymal stem cells (MSC), a cell population contributing to tissue growth and regeneration. To address these issues, we investigated the toxic effects of selected NP (Ag, ZnO, and CuO) in mouse MSC. MSC were treated with various doses of NP for 4 h, 24 h, and 48 h and multiple endpoints were analyzed. Reactive oxygen species were generated after 48 h CuO NP exposure. Lipid peroxidation was induced after 4 h and 24 h treatment, regardless of NP and/or tested dose. DNA fragmentation and oxidation induced by Ag NP showed dose responses for all the periods. For other NP, the effects were observed for shorter exposure times. The impact on the frequency of micronuclei was weak. All the tested NP increased the sensitivity of MSC to apoptosis. The cell cycle was most affected after 24 h, particularly for Ag NP treatment. In summary, the tested NP induced numerous adverse changes in MSC. These results should be taken into consideration when planning the use of NP in medical applications where MSC are involved.

Department of Genetic Toxicology and Epigenetics Institute of Experimental Medicine CAS 142 00 Prague Czech Republic

Department of Nanotoxicology and Molecular Epidemiology Institute of Experimental Medicine CAS 142 00 Prague Czech Republic

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McIntyre R.A. Common Nano-Materials and Their Use in Real World Applications. Sci. Prog. 2012;95:1–22. doi: 10.3184/003685012X13294715456431. PubMed DOI PMC

Beyth N., Houri-Haddad Y., Domb A., Khan W., Hazan R. Alternative Antimicrobial Approach: Nano-Antimicrobial Materials. Evid.-Based Complement. Altern. Med. 2015;2015:246012. doi: 10.1155/2015/246012. PubMed DOI PMC

Oyarzun-Ampuero F., Vidal A., Concha M., Morales J., Orellana S., Moreno-Villoslada I. Nanoparticles for the Treatment of Wounds. Curr. Pharm. Des. 2015;21:4329–4341. doi: 10.2174/1381612821666150901104601. PubMed DOI

Ajdary M., Moosavi M.A., Rahmati M., Falahati M., Mahboubi M., Mandegary A., Jangjoo S., Mohammadinejad R., Varma R.S. Health Concerns of Various Nanoparticles: A Review of Their in Vitro and in Vivo Toxicity. Nanomaterials. 2018;8:634. doi: 10.3390/nano8090634. PubMed DOI PMC

Abdal Dayem A., Lee S.B., Cho S.-G. The Impact of Metallic Nanoparticles on Stem Cell Proliferation and Differentiation. Nanomaterials. 2018;8:761. doi: 10.3390/nano8100761. PubMed DOI PMC

Zhou X., Yuan L., Wu C., Chen C., Luo G., Deng J., Mao Z. Recent review of the effect of nanomaterials on stem cells. RSC Adv. 2018;8:17656–17676. doi: 10.1039/C8RA02424C. PubMed DOI PMC

Bacakova L., Zarubova J., Travnickova M., Musilkova J., Pajorova J., Slepicka P., Kasalkova N.S., Svorcik V., Kolska Z., Motarjemi H., et al. Stem cells: Their source, potency and use in regenerative therapies with focus on adipose-derived stem cells—A review. Biotechnol. Adv. 2018;36:1111–1126. doi: 10.1016/j.biotechadv.2018.03.011. PubMed DOI

Abumaree M., Al Jumah M., Pace R.A., Kalionis B. Immunosuppressive Properties of Mesenchymal Stem Cells. Stem Cell Rev. Rep. 2011;8:375–392. doi: 10.1007/s12015-011-9312-0. PubMed DOI

English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol. Cell Biol. 2012;91:19–26. doi: 10.1038/icb.2012.56. PubMed DOI

Holan V., Hermankova B., Bohacova P., Kossl J., Chudickova M., Hajkova M., Krulova M., Zajicova A., Javorkova E. Distinct Immunoregulatory Mechanisms in Mesenchymal Stem Cells: Role of the Cytokine Environment. Stem Cell Rev. Rep. 2016;12:654–663. doi: 10.1007/s12015-016-9688-y. PubMed DOI

Sánchez-López E., Gomes D., Esteruelas G., Bonilla L., Lopez-Machado A.L., Galindo R., Cano A., Espina M., Ettcheto M., Camins A., et al. Metal-Based Nanoparticles as Antimicrobial Agents: An Overview. Nanomaterials. 2020;10:292. doi: 10.3390/nano10020292. PubMed DOI PMC

Helmlinger J., Sengstock C., Groß-Heitfeld C., Mayer C., Schildhauer T.A., Köller M., Epple M. Silver nanoparticles with different size and shape: Equal cytotoxicity, but different antibacterial effects. RSC Adv. 2016;6:18490–18501. doi: 10.1039/C5RA27836H. DOI

Breisch M., Grasmik V., Loza K., Pappert K., Rostek A., Ziegler N., Ludwig A., Heggen M., Epple M., Tiller J.C., et al. Bimetallic silver–platinum nanoparticles with combined osteo-promotive and antimicrobial activity. Nanotechnology. 2019;30:305101. doi: 10.1088/1361-6528/ab172b. PubMed DOI

Wan R., Chu S., Wang X., Lei L., Tang H., Hu G., Dong L., Li D., Gu H. Study on the osteogenesis of rat mesenchymal stem cells and the long-term antibacterial activity of Staphylococcus epidermidis on the surface of silver-rich TiN /Ag modified titanium alloy. J. Biomed. Mater. Res. Part B Appl. Biomater. 2020;108:3008–3021. doi: 10.1002/jbm.b.34630. PubMed DOI

Cioffi N., Torsi L., Ditaranto N., Tantillo G., Ghibelli L., Sabbatini L., Bleve-Zacheo T., D’Alessio M., Zambonin P.G., Traversa E. Copper Nanoparticle/Polymer Composites with Antifungal and Bacteriostatic Properties. Chem. Mater. 2005;17:5255–5262. doi: 10.1021/cm0505244. DOI

Ren G., Hu D., Cheng E.W., Vargas-Reus M.A., Reip P., Allaker R.P. Characterisation of copper oxide nanoparticles for antimicrobial applications. Int. J. Antimicrob. Agents. 2009;33:587–590. doi: 10.1016/j.ijantimicag.2008.12.004. PubMed DOI

Gunawan C., Teoh W.Y., Marquis C., Amal R. Cytotoxic Origin of Copper(II) Oxide Nanoparticles: Comparative Studies with Micron-Sized Particles, Leachate, and Metal Salts. ACS Nano. 2011;5:7214–7225. doi: 10.1021/nn2020248. PubMed DOI

Limbach L.K., Wick P., Manser P., Grass R.N., Bruinink A., Stark W.J. Exposure of Engineered Nanoparticles to Human Lung Epithelial Cells: Influence of Chemical Composition and Catalytic Activity on Oxidative Stress. Environ. Sci. Technol. 2007;41:4158–4163. doi: 10.1021/es062629t. PubMed DOI

Karlsson H.L., Cronholm P., Gustafsson J., Möller L. Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon Nanotubes. Chem. Res. Toxicol. 2008;21:1726–1732. doi: 10.1021/tx800064j. PubMed DOI

Murgia A., Mancuso L., Manis C., Caboni P., Cao G. GC-MS metabolomics analysis of mesenchymal stem cells treated with copper oxide nanoparticles. Toxicol. Mech. Methods. 2016;26:611–619. doi: 10.1080/15376516.2016.1220654. PubMed DOI

Fahmy B., Cormier S.A. Copper oxide nanoparticles induce oxidative stress and cytotoxicity in airway epithelial cells. Toxicol. Vitr. 2009;23:1365–1371. doi: 10.1016/j.tiv.2009.08.005. PubMed DOI PMC

Siddiqui M., Alhadlaq H., Ahmad J., Al-Khedhairy A., Musarrat J., Ahamed M. Copper Oxide Nanoparticles Induced Mitochondria Mediated Apoptosis in Human Hepatocarcinoma Cells. PLoS ONE. 2013;8:e69534. doi: 10.1371/journal.pone.0069534. PubMed DOI PMC

Le Blanc K. Mesenchymal stromal cells: Tissue repair and immune modulation. Cytotherapy. 2006;8:559–561. doi: 10.1080/14653240601045399. PubMed DOI

Sasaki M., Abe R., Fujita Y., Ando S., Inokuma D., Shimizu H. Mesenchymal Stem Cells Are Recruited into Wounded Skin and Contribute to Wound Repair by Transdifferentiation into Multiple Skin Cell Type. J. Immunol. 2008;180:2581–2587. doi: 10.4049/jimmunol.180.4.2581. PubMed DOI

Politano A.D., Campbell K.T., Rosenberger L.H., Sawyer R.G. Use of Silver in the Prevention and Treatment of Infections: Silver Review. Surg. Infect. 2013;14:8–20. doi: 10.1089/sur.2011.097. PubMed DOI PMC

Kumar R., Umar A., Kumar G., Nalwa H.S. Antimicrobial properties of ZnO nanomaterials: A review. Ceram. Int. 2017;43:3940–3961. doi: 10.1016/j.ceramint.2016.12.062. DOI

Altoé L.S., Alves R.S., Sarandy M.M., Morais-Santos M., Novaes R.D., Gonçalves R.V. Does antibiotic use accelerate or retard cutaneous repair? A systematic review in animal models. PLoS ONE. 2019;14:e0223511. doi: 10.1371/journal.pone.0223511. PubMed DOI PMC

Matsumoto H., Wada T., Fukunaga K., Yoshihiro S., Matsuyama H., Naito K. Bax to Bcl-2 Ratio and Ki-67 Index are Useful Predictors of Neoadjuvant Chemoradiation Therapy in Bladder Cancer. Jpn. J. Clin. Oncol. 2004;34:124–130. doi: 10.1093/jjco/hyh026. PubMed DOI

Echalar B., Dostalova D., Palacka K., Javorkova E., Hermankova B., Cervena T., Zajicova A., Holan V., Rossner P. Effects of antimicrobial metal nanoparticles on characteristics and function properties of mouse mesenchymal stem cells. Toxicol. Vitr. 2023;87:105536. doi: 10.1016/j.tiv.2022.105536. PubMed DOI

Porubska B., Vasek D., Somova V., Hajkova M., Hlaviznova M., Tlapakova T., Holan V., Krulova M. Sertoli Cells Possess Immunomodulatory Properties and the Ability of Mitochondrial Transfer Similar to Mesenchymal Stromal Cells. Stem Cell Rev. Rep. 2021;17:1905–1916. doi: 10.1007/s12015-021-10197-9. PubMed DOI

Jensen K.A. The NANOGENOTOX Dispersion Protocol for NANoREG. National Research Centre for the Working Environment; Copenhagen, Denmark: 2014.

Hanzalova K., Rossner P., Sram R.J. Oxidative damage induced by carcinogenic polycyclic aromatic hydrocarbons and organic extracts from urban air particulate matter. Mutat. Res. Toxicol. Environ. Mutagen. 2010;696:114–121. doi: 10.1016/j.mrgentox.2009.12.018. PubMed DOI

Rossner P., Libalova H., Vrbova K., Cervena T., Rossnerova A., Elzeinova F., Milcova A., Novakova Z., Topinka J. Genotoxicant exposure, activation of the aryl hydrocarbon receptor, and lipid peroxidation in cultured human alveolar type II A549 cells. Mutat. Res. Toxicol. Environ. Mutagen. 2020;853:503173. doi: 10.1016/j.mrgentox.2020.503173. PubMed DOI

Novotna B., Topinka J., Solansky I., Chvatalova I., Lnenickova Z., Sram R.J. Impact of air pollution and genotype variability on DNA damage in Prague policemen. Toxicol. Lett. 2007;172:37–47. doi: 10.1016/j.toxlet.2007.05.013. PubMed DOI

Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262. PubMed DOI

Worldwide M.I. Dynamic Light Scattering: Common Terms Define. Malwern Instruments Limited; Malvern, UK: 2011. Inform white paper.

Holan V., Trosan P., Cejka C., Javorkova E., Zajicova A., Hermankova B., Chudickova M., Cejkova J. A Comparative Study of the Therapeutic Potential of Mesenchymal Stem Cells and Limbal Epithelial Stem Cells for Ocular Surface Reconstruction: MSCs and LSCs for Ocular Surface Reconstruction. STEM CELLS Transl. Med. 2015;4:1052–1063. doi: 10.5966/sctm.2015-0039. PubMed DOI PMC

Magdolenova Z., Collins A., Kumar A., Dhawan A., Stone V., Dusinska M. Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles. Nanotoxicology. 2014;8:233–278. doi: 10.3109/17435390.2013.773464. PubMed DOI

Poetsch A.R. The genomics of oxidative DNA damage, repair, and resulting mutagenesis. Comput. Struct. Biotechnol. J. 2020;18:207–219. doi: 10.1016/j.csbj.2019.12.013. PubMed DOI PMC

Sengstock C., Diendorf J., Epple M., Schildhauer T.A., Köller M. Effect of silver nanoparticles on human mesenchymal stem cell differentiation. Beilstein J. Nanotechnol. 2014;5:2058–2069. doi: 10.3762/bjnano.5.214. PubMed DOI PMC

Hackenberg S., Scherzed A., Kessler M., Hummel S., Technau A., Froelich K., Ginzkey C., Koehler C., Hagen R., Kleinsasser N. Silver nanoparticles: Evaluation of DNA damage, toxicity and functional impairment in human mesenchymal stem cells. Toxicol. Lett. 2011;201:27–33. doi: 10.1016/j.toxlet.2010.12.001. PubMed DOI

Liu X., He W., Fang Z., Kienzle A., Feng Q. Influence of Silver Nanoparticles on Osteogenic Differentiation of Human Mesenchymal Stem Cells. J. Biomed. Nanotechnol. 2014;10:1277–1285. doi: 10.1166/jbn.2014.1824. PubMed DOI

Zhang R., Lee P., Lui V.C.H., Chen Y., Liu X., Lok C.N., To M., Yeung K., Wong K.K. Silver nanoparticles promote osteogenesis of mesenchymal stem cells and improve bone fracture healing in osteogenesis mechanism mouse model. Nanomed. Nanotechnol. Biol. Med. 2015;11:1949–1959. doi: 10.1016/j.nano.2015.07.016. PubMed DOI

Pérez-Díaz M.A., Silva-Bermudez P., Jiménez-López B., Martínez-López V., Melgarejo-Ramírez Y., Brena-Molina A., Ibarra C., Baeza I., Martínez-Pardo M.E., Reyes-Frías M.L., et al. Silver-pig skin nanocomposites and mesenchymal stem cells: Suitable antibiofilm cellular dressings for wound healing. J. Nanobiotechnology. 2018;16:2. doi: 10.1186/s12951-017-0331-0. PubMed DOI PMC

Patil S., Singh N. Antibacterial silk fibroin scaffolds with green synthesized silver nanoparticles for osteoblast proliferation and human mesenchymal stem cell differentiation. Colloids Surf. B Biointerfaces. 2018;176:150–155. doi: 10.1016/j.colsurfb.2018.12.067. PubMed DOI

Tian J., Wong K.K., Ho C.M., Lok C.N., Yu W.Y., Che C.M., Cliu J.F., Tam P.K. Topical delivery of silver nanoparticles promotes wound healing. ChemMedChem. 2007;2:129–136. doi: 10.1002/cmdc.200600171. PubMed DOI

Paterson T.E., Shi R., Tian J., Harrison C.J., Mendes M.D.S., Hatton P.V., Li Z., Ortega I. Electrospun Scaffolds Containing Silver-Doped Hydroxyapatite with Antimicrobial Properties for Applications in Orthopedic and Dental Bone Surgery. J. Funct. Biomater. 2020;11:58. doi: 10.3390/jfb11030058. PubMed DOI PMC

Mancuso L., Cao G. Acute toxicity test of CuO nanoparticles using human mesenchymal stem cells. Toxicol. Mech. Methods. 2014;24:449–454. doi: 10.3109/15376516.2014.928920. PubMed DOI

Zhang W., Jiang P., Chen W., Zheng B., Mao Z., Antipov A., Correia M., Larsen E.H., Gao C. Genotoxicity of Copper Oxide Nanoparticles with Different Surface Chemistry on Rat Bone Marrow Mesenchymal Stem Cells. J. Nanosci. Nanotechnol. 2016;16:5489–5497. doi: 10.1166/jnn.2016.11753. PubMed DOI

Rodríguez J.P., Ríos S., González M. Modulation of the proliferation and differentiation of human mesenchymal stem cells by copper. J. Cell. Biochem. 2002;85:92–100. doi: 10.1002/jcb.10111. PubMed DOI

Syama S., Sreekanth P.J., Varma H.K., Mohanan P.V. Zinc oxide nanoparticles induced oxidative stress in mouse bone marrow mesenchymal stem cells. Toxicol. Mech. Methods. 2014;24:644–653. doi: 10.3109/15376516.2014.956914. PubMed DOI

Ickrath P., Wagner M., Scherzad A., Gehrke T., Burghartz M., Hagen R., Radeloff K., Kleinsasser N., Hackenberg S. Time-Dependent Toxic and Genotoxic Effects of Zinc Oxide Nanoparticles after Long-Term and Repetitive Exposure to Human Mesenchymal Stem Cells. Int. J. Environ. Res. Public Health. 2017;14:1590. doi: 10.3390/ijerph14121590. PubMed DOI PMC

Milne G.L., Dai Q., Roberts L.J. The isoprostanes—25 years later. Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids. 2015;1851:433–445. doi: 10.1016/j.bbalip.2014.10.007. PubMed DOI PMC

Šulinskienė J., Bernotienė R., Baranauskienė D., Naginienė R., Stanevičienė I., Kašauskas A., Ivanov L. Effect of Zinc on the Oxidative Stress Biomarkers in the Brain of Nickel-Treated Mice. Oxidative Med. Cell. Longev. 2019;2019:8549727. doi: 10.1155/2019/8549727. PubMed DOI PMC

Plesca D., Mazumder S., Almasan A. Methods in Enzymology. Volume 446. Elsevier; Amsterdam, The Netherlands: 2008. Chapter 6 DNA Damage Response and Apoptosis; pp. 107–122. PubMed DOI PMC

Alavi M., Nokhodchi A. An overview on antimicrobial and wound healing properties of ZnO nanobiofilms, hydrogels, and bionanocomposites based on cellulose, chitosan, and alginate polymers. Carbohydr. Polym. 2019;227:115349. doi: 10.1016/j.carbpol.2019.115349. PubMed DOI