{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:33:06Z","timestamp":1783776786880,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SIP","award":["#20180597"],"award-info":[{"award-number":["#20180597"]}]},{"name":"Escuela Superior de Medicina"},{"DOI":"10.13039\/501100003069","name":"Instituto Polit\u00e9cnico Nacional","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003069","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human exposure to titanium dioxide nanoparticles (TiO2 NPs) is common. These NPs are used in cosmetics, paint, food, and other products. Their nanometric size (&lt;100 nm) allows entry into the bloodstream, from which they can reach organs and cells throughout the body. Although TiO2 NPs have been reported to damage certain cell lines and organs and to alter cellular function, their impact on human menstrual blood mesenchymal stem cells (hMB-MSCs) is unknown. This study evaluated the effects of TiO2 NPs on viability, proliferation, morphology, membrane-marker expression, and reactive oxygen species (ROS) production in primary cultures of hMB-MSCs derived from menstrual blood. Cells were exposed to different concentrations of TiO2 NPs for 3, 7, and 14 days. TiO2 NPs decreased hMB-MSC viability and proliferation in a concentration- and time-dependent manner. Cellular viability was reduced by up to 6%, 11%, and 18% at 3, 7, and 14 days, respectively (statistically significant vs. control). Cellular proliferation decreased by 3%, 5%, and 33% at 15.63, 62.5, and 250 \u03bcg\/mL TiO2, respectively. TiO2 NPs were internalized and observed in the cytoplasm, forming perinuclear aggregates. NP-exposed cells showed reduced membrane expression of CD73 (7.9% decrease) and CD90 (25.72% decrease) compared with control cells. Finally, TiO2 NPs at 15.63, 62.5, and 250 \u00b5g\/mL reduced ROS generation by 56.79%, 62.79%, and 53.35%, respectively, after 4 h (statistically significant vs. control). In summary, exposure to high concentrations of TiO2 NPs leads to intracellular nanoparticle deposits and alters key functions of human menstrual blood mesenchymal stem cells, including immunomodulation, immune protection, molecular behavior, cell differentiation, and regenerative capacity.<\/jats:p>","DOI":"10.3390\/ijms262211168","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T11:17:27Z","timestamp":1763551047000},"page":"11168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Toxicological Effects of Titanium Dioxide Nanoparticles on Human Menstrual Blood Mesenchymal Stem Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8631-3099","authenticated-orcid":false,"given":"Alberto","family":"Parra-Barrera","sequence":"first","affiliation":[{"name":"Laboratorio de Medicina Regenerativa y Estudios del C\u00e1ncer, Departamento de Investigaci\u00f3n y Posgrado, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"},{"name":"Immunotherapy, Regenerative Medicine, Laboratorio QuantumLab, Departamento de Investigaci\u00f3n, Puerto Vallarta 48313, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1090-5084","authenticated-orcid":false,"given":"Rebeca","family":"L\u00f3pez-Marure","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Romero-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Immunotherapy, Regenerative Medicine, Laboratorio QuantumLab, Departamento de Investigaci\u00f3n, Puerto Vallarta 48313, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-8566","authenticated-orcid":false,"given":"Claudia Camelia","family":"Calzada-Mendoza","sequence":"additional","affiliation":[{"name":"Laboratorio de Se\u00f1alizaci\u00f3n Celular, Departamento de Investigaci\u00f3n y Posgrado, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7289-0821","authenticated-orcid":false,"given":"Jos\u00e9","family":"Arellano-Galindo","sequence":"additional","affiliation":[{"name":"Departamento de Medicina, Centro Interdisciplinario de Ciencias de la Salud Unidad Milpa Alta, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 12000, Mexico"},{"name":"Laboratorio de Virolog\u00eda Cl\u00ednica Experimental, Unidad de Investigaci\u00f3n en Enfermedades Infecciosas, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, Ciudad de M\u00e9xico 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0368-9045","authenticated-orcid":false,"given":"Ricardo","family":"Rangel-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Corporativo ExomeLab\u2013Biotecnologia Exosomal, Ciudad de M\u00e9xico 09479, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4137-0652","authenticated-orcid":false,"given":"Gisela","family":"Guti\u00e9rrez-Iglesias","sequence":"additional","affiliation":[{"name":"Laboratorio de Medicina Regenerativa y Estudios del C\u00e1ncer, Departamento de Investigaci\u00f3n y Posgrado, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.taap.2011.11.010","article-title":"Nanotoxicology and in vitro studies: The need of the hour","volume":"258","author":"Arora","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1634\/stemcells.22-4-625","article-title":"Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood","volume":"22","author":"Bieback","year":"2004","journal-title":"Stem Cells"},{"key":"ref_3","first-page":"7","article-title":"Titanium particles enhanced osteoclast differentiation and osteoclast bone resorption activity in vitro","volume":"5","author":"Bo","year":"2013","journal-title":"J. Dent. Oral Hyg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1634\/stemcells.2007-0197","article-title":"Concise views: Mesenchymal stem cells: Their phenotype, differentiation capacity, immunological features, and potential for homing","volume":"25","author":"Chamberlain","year":"2007","journal-title":"Stem Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"015008","DOI":"10.1088\/1468-6996\/14\/1\/015008","article-title":"Role of toll-like receptors 3, 4 and 7 in cellular uptake and response to titanium dioxide nanoparticles","volume":"14","author":"Chen","year":"2013","journal-title":"Sci. Technol. Adv. Mater."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e213","DOI":"10.1016\/j.jcms.2013.01.021","article-title":"Adipose derived mesenchymal stem cells: Their osteogenicity and osteoblast in vitro mineralization on titanium granule carriers","volume":"41","author":"Dahl","year":"2013","journal-title":"J. Cranio-Maxillofac. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/1529-0131(200101)44:1<85::AID-ANR12>3.0.CO;2-6","article-title":"Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age","volume":"44","author":"Luyten","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lopes, V.R., Loitto, V., Audinot, J.N., Bayat, N., Gutleb, A.C., and Cristobal, S. (2016). Dose-dependent autophagic effect of titanium dioxide nanoparticles in human HaCaT cells at non-cytotoxic levels. J. Nanobiotechnol., 14.","DOI":"10.1186\/s12951-016-0174-0"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1097\/00007890-196803000-00009","article-title":"Heterotopic transplants of bone marrow","volume":"6","author":"Friedenstein","year":"1968","journal-title":"Transplantation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0167-5729(02)00100-0","article-title":"The surface science of titanium dioxide","volume":"48","author":"Diebold","year":"2003","journal-title":"Surf. Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kuku, G., and Culha, M. (2017). Investigating the origin of toxic response in TiO2 nanoparticle-treated cells. Nanomaterials, 7.","DOI":"10.3390\/nano7040083"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.tiv.2009.12.007","article-title":"Activation of human neutrophils by titanium dioxide (TiO2) nanoparticles","volume":"24","author":"Chiasson","year":"2010","journal-title":"Toxicol. In Vitr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.biologicals.2018.06.004","article-title":"Evaluation of toll-like receptor 4 expression in human bone marrow mesenchymal stem cells by lipopolysaccharides from Shigella","volume":"55","author":"Hashemzadeh","year":"2018","journal-title":"Biologicals"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1002\/stem.1681","article-title":"Concise review: The surface markers and identity of human mesenchymal stem cells","volume":"32","author":"Lv","year":"2014","journal-title":"Stem Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s13287-021-02212-0","article-title":"Human mesenchymal stem cell treatment of premature ovarian failure: New challenges and opportunities","volume":"12","author":"Fu","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_16","first-page":"980","article-title":"How similar are human mesenchymal stem cells derived from different origins? A review of comparative studies","volume":"16","author":"Najmeh","year":"2021","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2174\/1574888X09666140709111444","article-title":"Mesenchymal stem cells in cartilage regeneration","volume":"9","author":"Savkovic","year":"2014","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1021\/tx200551u","article-title":"TiO2 nanoparticles induce dysfunction and activation of human endothelial cells","volume":"25","year":"2012","journal-title":"Chem. Res. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1182\/blood-2003-04-1291","article-title":"Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation","volume":"102","author":"Scherjon","year":"2003","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"El-Said, K.S., Ali, E.M., Kanehira, K., and Taniguchi, A. (2014). Molecular mechanism of DNA damage induced by titanium dioxide nanoparticles in toll-like receptor 3 or 4 expressing human hepatocarcinoma cell lines. J. Nanobiotechnol., 12.","DOI":"10.1186\/s12951-014-0048-2"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s12015-022-10493-y","article-title":"The therapeutic potential of human umbilical cord derived mesenchymal stem cells for the treatment of premature ovarian failure","volume":"19","author":"Umer","year":"2023","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"485","DOI":"10.2147\/TCRM.S410277","article-title":"Current and novel therapeutics for articular cartilage repair and regeneration","volume":"19","author":"Cong","year":"2023","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"104328","DOI":"10.1016\/j.etap.2023.104328","article-title":"DNA damage in workers exposed to pigment grade titanium dioxide (TiO2) and association with biomarkers of oxidative stress and inflammation","volume":"105","author":"Bonetta","year":"2024","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12989-017-0232-2","article-title":"Pro-inflammatory adjuvant properties of pigment-grade titanium dioxide particles are augmented by a genotype that potentiates interleukin-1\u03b2 processing","volume":"14","author":"Riedle","year":"2017","journal-title":"Part. Fibre Toxicol."},{"key":"ref_25","first-page":"3619","article-title":"Effects of titanium nanoparticles on adhesion, migration, proliferation, and differentiation of mesenchymal stem cells","volume":"8","author":"Hou","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7309","DOI":"10.1021\/es100417s","article-title":"Dispersion and stability optimization of TiO2 nanoparticles in cell culture media","volume":"44","author":"Ji","year":"2010","journal-title":"Environ. Sci. Technol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/jat.3342","article-title":"Cytotoxic and inflammatory responses of TiO2 nanoparticles on human peripheral blood mononuclear cells","volume":"36","author":"Kongseng","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"116020","DOI":"10.1016\/j.taap.2022.116020","article-title":"Titanium dioxide nanoparticles induced reactive oxygen species (ROS) related changes of metabolomics signatures in human normal bronchial epithelial (BEAS-2B) cells","volume":"444","author":"Zhang","year":"2022","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kheder, W., Soumya, S., and Samsudin, A. (2021). Impact of titanium dioxide particle size on macrophage production of intracellular reactive oxygen species. Arch. Oral Biol., 127.","DOI":"10.1016\/j.archoralbio.2021.105133"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bovari-Biri, J., A Miskei, J., Kover, Z., Steinerbrunner-Nagy, A., Kardos, K., Maroti, P.E., and Pongracz, J. (2025). Titanium dioxide nanoparticle-induced autophagy and its role in stem cell differentiation. Cells, 14.","DOI":"10.3390\/cells14020145"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Afonso, P., Castro, I., and Carvalho, M. (2025). Salt-Resilient Cowpeas: Early Identification Through Growth Parameters and Gene Expression at Germination Stage. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26051892"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Im, J.H., Lee, K.-Y., Seo, Y., Rhim, J., Dho, Y.-S., Yoo, B.C., Park, J.B., Shin, S.H., Yoo, H., and Kim, J.H. (2024). Titanium dioxide nanoparticles trigger mitochondrial-mediated apoptosis and oxidative stress in human mesenchymal stem cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063124"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wu, C., Zhang, T., Liang, J., Yin, J., Xiao, M., Han, D., Huang, S., Wang, S., and Meng, Y. (2024). Biodegradable and Ultra-High Expansion Ratio PPC-P Foams Achieved by Microcellular Foaming Using CO2 as Blowing Agent. Nanomaterials, 14.","DOI":"10.3390\/nano14131120"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nemmar, A., Holme, J.A., Rosas, I., Schwarze, P.E., and Alfaro-Moreno, E. (2013). Recent advances in particulate matter and nanoparticle toxicology: A review of the in vivo and in vitro studies. BioMed Res. Int., 2013.","DOI":"10.1155\/2013\/279371"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.redox.2017.12.011","article-title":"TiO2 nanoparticles cause mitochondrial dysfunction, activate inflammatory responses, and attenuate phagocytosis in macrophages: A proteomic and metabolomic insight","volume":"15","author":"Chen","year":"2018","journal-title":"Redox Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12347","DOI":"10.3390\/s120912347","article-title":"Multiple Applications of Alamar Blue as an Indicator of Metabolic Function and Cellular Health in Cell Viability Bioassays","volume":"12","author":"Rampersad","year":"2012","journal-title":"Sensors"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"84","DOI":"10.22203\/eCM.v022a07","article-title":"Adhesion and osteogenic differentiation of human mesenchymal stem cells on titanium nanopores","volume":"22","author":"Lavenus","year":"2011","journal-title":"Eur. Cell. Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/smll.200700595","article-title":"Cytotoxicity of nanoparticles","volume":"4","author":"Lewinski","year":"2008","journal-title":"Small"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"pdb-rot095489","DOI":"10.1101\/pdb.prot095489","article-title":"Analysis of Cell Viability by the Alamar Blue Assay","volume":"2018","author":"Kumar","year":"2018","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"pdb.prot087379","DOI":"10.1101\/pdb.prot087379","article-title":"Crystal Violet Assay for Determining Viability of Cultured Cells","volume":"2016","author":"Feoktistova","year":"2016","journal-title":"Cold Spring Harb. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:24:47Z","timestamp":1763702687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":40,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211168"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211168","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}