{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:41:13Z","timestamp":1791646873176,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Regional Development Fund","award":["VEGA 1\/0281\/23"],"award-info":[{"award-number":["VEGA 1\/0281\/23"]}]},{"name":"European Regional Development Fund","award":["UK\/196\/2023"],"award-info":[{"award-number":["UK\/196\/2023"]}]},{"name":"resources of the European Regional Development Fund, the Slovak Scientific Grant Agency","award":["VEGA 1\/0281\/23"],"award-info":[{"award-number":["VEGA 1\/0281\/23"]}]},{"name":"resources of the European Regional Development Fund, the Slovak Scientific Grant Agency","award":["UK\/196\/2023"],"award-info":[{"award-number":["UK\/196\/2023"]}]},{"DOI":"10.13039\/100007594","name":"Comenius University in Bratislava","doi-asserted-by":"publisher","award":["VEGA 1\/0281\/23"],"award-info":[{"award-number":["VEGA 1\/0281\/23"]}],"id":[{"id":"10.13039\/100007594","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007594","name":"Comenius University in Bratislava","doi-asserted-by":"publisher","award":["UK\/196\/2023"],"award-info":[{"award-number":["UK\/196\/2023"]}],"id":[{"id":"10.13039\/100007594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Urine-derived stem cells (UdSCs) possess a remarkable anti-inflammatory and immune-modulating activity. However, the clinical significance of UdSCs in autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is yet to be explored. Hence, we tested the UdSCs response to an articular RA microenvironment. To simulate the inflamed RA joint more authentically in vitro, we treated cells with rheumatoid synovial fluids (RASFs) collected from RA patients, serum deprivation, acidosis (pH 7.0 and 6.5), and their combinations. Firstly, the RASFs pro-inflammatory status was assessed by cytokine quantification. Then, UdSCs were exposed to the RA environmental factors for 48 h and cell proliferation, gene expression and secretion of immunomodulatory factors were evaluated. The immunosuppressive potential of pre-conditioned UdSCs was also assessed via co-cultivation with activated peripheral blood mononuclear cells (PBMCs). In all experimental conditions, UdSCs\u2019 proliferation was not affected. Conversely, extracellular acidosis considerably impaired the viability\/proliferation of adipose tissue-derived stem cells (ATSCs). In the majority of cases, exposure to RA components led to the upregulated expression of IL-6, TSG6, ICAM-1, VCAM-1, and PD-L1, all involved in immunomodulation. Upon RASFs and acidic stimulation, UdSCs secreted higher levels of immunomodulatory cytokines: IL-6, IL-8, MCP-1, RANTES, GM-CSF, and IL-4. Furthermore, RASFs and combined pretreatment with RASFs and acidosis promoted the UdSCs-mediated immunosuppression and the proliferation of activated PBMCs was significantly inhibited. Altogether, our data indicate that the RA microenvironment certainly has the capacity to enhance UdSCs\u2019 immunomodulatory function. For potential preclinical\/clinical applications, the intra-articular injection might be a reasonable approach to maximize UdSCs\u2019 therapeutic efficiency in the RA treatment.<\/jats:p>","DOI":"10.3390\/ijms242115856","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T03:29:33Z","timestamp":1698809373000},"page":"15856","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Rheumatoid Synovial Fluid and Acidic Extracellular pH Modulate the Immunomodulatory Activity of Urine-Derived Stem Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9530-6499","authenticated-orcid":false,"given":"Michaela","family":"Cehakova","sequence":"first","affiliation":[{"name":"National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia"},{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-301X","authenticated-orcid":false,"given":"Dana","family":"Ivanisova","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Strecanska","sequence":"additional","affiliation":[{"name":"National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia"},{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9356-6219","authenticated-orcid":false,"given":"Jana","family":"Plava","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"},{"name":"Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Varchulova Novakova","sequence":"additional","affiliation":[{"name":"National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia"},{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1989-7423","authenticated-orcid":false,"given":"Andreas","family":"Nicodemou","sequence":"additional","affiliation":[{"name":"National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia"},{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7889-4898","authenticated-orcid":false,"given":"Stefan","family":"Harsanyi","sequence":"additional","affiliation":[{"name":"National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia"},{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3484-0002","authenticated-orcid":false,"given":"Martina","family":"Culenova","sequence":"additional","affiliation":[{"name":"National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia"},{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sona","family":"Bernatova","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5074-9621","authenticated-orcid":false,"given":"Lubos","family":"Danisovic","sequence":"additional","affiliation":[{"name":"National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia"},{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1517\/14712598.2010.519333","article-title":"Mesenchymal stem cells: Biological properties and clinical applications","volume":"10","author":"Elvira","year":"2010","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nbt.2816","article-title":"Mesenchymal stem cells: Immune evasive, not immune privileged","volume":"32","author":"Ankrum","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/nyas.12815","article-title":"The immunomodulatory function of mesenchymal stem cells: Mode of action and pathways","volume":"1351","author":"Uccelli","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1038\/cdd.2012.26","article-title":"Mesenchymal stem cells: A double-edged sword in regulating immune responses","volume":"19","author":"Li","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.stem.2007.11.014","article-title":"Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide","volume":"2","author":"Ren","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.4049\/jimmunol.0902023","article-title":"Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression","volume":"184","author":"Ren","year":"2010","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.3389\/fimmu.2019.01482","article-title":"Rheumatoid Synovial Fluids Regulate the Immunomodulatory Potential of Adipose-Derived Mesenchymal Stem Cells Through a TNF\/NF-\u03baB-Dependent Mechanism","volume":"10","author":"Sayegh","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1186\/s13287-021-02664-4","article-title":"Role of PD-L1 in licensing immunoregulatory function of dental pulp mesenchymal stem cells","volume":"12","author":"Bertani","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/cdd.2013.158","article-title":"Immunobiology of mesenchymal stem cells","volume":"21","author":"Ma","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00296-019-04296-7","article-title":"Secretory factors produced by adipose mesenchymal stem cells downregulate Th17 and increase Treg cells in peripheral blood mononuclear cells from rheumatoid arthritis patients","volume":"39","author":"Vasilev","year":"2019","journal-title":"Rheumatol. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/1479-5876-12-157","article-title":"Intra-articular injection of mesenchymal stem cells leads to reduced inflammation and cartilage damage in murine antigen-induced arthritis","volume":"12","author":"Kehoe","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.ebiom.2019.08.073","article-title":"Meta-analysis of preclinical studies of mesenchymal stromal cells to treat rheumatoid arthritis","volume":"47","author":"Liu","year":"2019","journal-title":"eBioMedicine"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lopez-Santalla, M., Fernandez-Perez, R., and Garin, M.I. (2020). Mesenchymal Stem\/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications. Cells, 9.","DOI":"10.3390\/cells9081852"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.jcyt.2021.10.003","article-title":"Rheumatoid arthritis: From synovium biology to cell-based therapy","volume":"24","author":"Debreova","year":"2022","journal-title":"Cytotherapy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/ca.22980","article-title":"Rheumatoid arthritis in review: Clinical, anatomical, cellular and molecular points of view","volume":"31","author":"Sharif","year":"2018","journal-title":"Clin. Anat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jim.2013.08.007","article-title":"Chemokine and cytokine levels in osteoarthritis and rheumatoid arthritis synovial fluid","volume":"396","author":"Hampel","year":"2013","journal-title":"J. Immunol. Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/art.1780140407","article-title":"Synovial fluid pH, lactate, oxygen and carbon dioxide partial pressure in various joint diseases","volume":"14","author":"Treuhaft","year":"1971","journal-title":"Arthritis Rheum."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1002\/1529-0131(200107)44:7<1540::AID-ART277>3.0.CO;2-7","article-title":"Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: Implications for targeting of therapeutic genes to the inflamed joint","volume":"44","author":"Hollander","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1136\/ard.2009.119776","article-title":"Synovial tissue hypoxia and inflammation in vivo","volume":"69","author":"Ng","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1016\/j.juro.2008.07.023","article-title":"Urine derived cells are a potential source for urological tissue reconstruction","volume":"180","author":"Zhang","year":"2008","journal-title":"J. Urol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Culenova, M., Nicodemou, A., Novakova, Z.V., Debreova, M., Smolinsk\u00e1, V., Bernatova, S., Ivanisova, D., Novotna, O., Vasicek, J., and Varga, I. (2021). Isolation, Culture and Comprehensive Characterization of Biological Properties of Human Urine-Derived Stem Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212503"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1093\/ecco-jcc\/jjz200","article-title":"Immunomodulatory Effect of Urine-derived Stem Cells on Inflammatory Bowel Diseases via Downregulating Th1\/Th17 Immune Responses in a PGE2-dependent Manner","volume":"14","author":"Zhou","year":"2020","journal-title":"J. Crohns Colitis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3566","DOI":"10.21037\/tau-21-506","article-title":"Functional characterization of the immunomodulatory properties of human urine-derived stem cells","volume":"10","author":"Wu","year":"2021","journal-title":"Transl. Androl. Urol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1186\/s13075-021-02619-3","article-title":"Isopsoralen ameliorates rheumatoid arthritis by targeting MIF","volume":"23","author":"Han","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1093\/rheumatology\/35.5.416","article-title":"Difference in expression of the plasminogen activation system in synovial tissue of patients with rheumatoid arthritis and osteoarthritis","volume":"35","author":"Ronday","year":"1996","journal-title":"Br. J. Rheumatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/BF01534595","article-title":"Production of soluble ICAM-1 by mononuclear cells from patients with rheumatoid arthritis patients","volume":"18","author":"Shingu","year":"1994","journal-title":"Inflammation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"94","DOI":"10.46497\/ArchRheumatol.2022.8891","article-title":"Synovial fluid niche promoted differentiation of dental follicle mesenchymal stem cells toward chondrogenesis in rheumatoid arthritis","volume":"37","author":"Elbe","year":"2022","journal-title":"Arch. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hazehara-Kunitomo, Y., Hara, E.S., Ono, M., Aung, K.T., Komi, K., Pham, H.T., Akiyama, K., Okada, M., Oohashi, T., and Matsumoto, T. (2019). Acidic Pre-Conditioning Enhances the Stem Cell Phenotype of Human Bone Marrow Stem\/Progenitor Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051097"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1634\/stemcells.2006-0548","article-title":"Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism","volume":"25","author":"Djouad","year":"2007","journal-title":"Stem Cells Dayt. Ohio"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1182\/blood-2010-12-327353","article-title":"Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2\/NF-\u03baB signaling in resident macrophages","volume":"118","author":"Choi","year":"2011","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5187","DOI":"10.1038\/s41598-017-04766-7","article-title":"TSG-6 Secreted by Human Adipose Tissue-derived Mesenchymal Stem Cells Ameliorates DSS-induced colitis by Inducing M2 Macrophage Polarization in Mice","volume":"7","author":"Song","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1002\/eji.201343668","article-title":"Human mesenchymal stromal cells modulate T-cell responses through TNF-\u03b1-mediated activation of NF-\u03baB","volume":"44","author":"Dorronsoro","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"ref_33","first-page":"277","article-title":"Vasculature of the normal and arthritic synovial joint","volume":"16","author":"Haywood","year":"2001","journal-title":"Histol. Histopathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1089\/jir.2008.0027","article-title":"Monocyte chemoattractant protein-1 (MCP-1): An overview","volume":"29","author":"Deshmane","year":"2009","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4546","DOI":"10.4049\/jimmunol.163.8.4546","article-title":"Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction","volume":"163","author":"Lubberts","year":"1999","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1172\/JCI7739","article-title":"IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion","volume":"105","author":"Lubberts","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"345","DOI":"10.5152\/tud.2017.93797","article-title":"Isolation and in vitro cultivation of human urine-derived cells: An alternative stem cell source","volume":"43","author":"Tayhan","year":"2017","journal-title":"Turk. J. Urol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Plava, J., Cihova, M., Burikova, M., Bohac, M., Adamkov, M., Drahosova, S., Rusnakova, D., Pindak, D., Karaba, M., and Simo, J. (2020). Permanent Pro-Tumorigenic Shift in Adipose Tissue-Derived Mesenchymal Stromal Cells Induced by Breast Malignancy. Cells, 9.","DOI":"10.3390\/cells9020480"},{"key":"ref_39","first-page":"e53265","article-title":"Assessment of the Immunomodulatory Properties of Human Mesenchymal Stem Cells (MSCs)","volume":"106","author":"Hsu","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1038\/nprot.2007.296","article-title":"Monitoring lymphocyte proliferation in vitro and in vivo with the intracellular fluorescent dye carboxyfluorescein diacetate succinimidyl ester","volume":"2","author":"Quah","year":"2007","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15856\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:15:26Z","timestamp":1760130926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15856"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,1]]},"references-count":40,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115856"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115856","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,1]]}}}