{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T19:45:22Z","timestamp":1786823122932,"version":"build-2736575974"},"reference-count":63,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Background: Radiation cystitis (RC) results from chronic inflammation, fibrosis, and vascular damage. The urinary symptoms it causes have a serious impact on patients\u2019 quality of life. Despite the improvement in irradiation techniques, the incidence of radiation cystitis remains stable over time, and the therapeutic possibilities remain limited. Mesenchymal stem\/stromal cells (MSC) appear to offer2 a promising therapeutic approach by promoting tissue repair through their paracrine action via extracellular vesicles (MSC-EVs) or conditioned medium from human mesenchymal stromal cells (MSC-CM). We assess the therapeutic potential of MSC-EVs or MSC-CM in an in vitro model of RC. Methods:in vitro RC was induced by irradiation of human bladder fibroblasts (HUBF) with the small-animal radiation research platform (SARRP). HUBF were induced towards an RC phenotype after 3 \u00d7 3.5 Gy irradiation in the presence of either MSC-EVs or MSC-CM, to assess their effect on fibrosis, angiogenesis, and inflammatory markers. Results: Our data revealed in vitro a higher therapeutic potential of MSC-EVs and MSC-CM in prevention of RC. This was confirmed by down-regulation of \u03b1-SMA and CTGF transcription, and the induction of the secretion of anti-fibrotic cytokines, such as IFN\u03b3, IL10 and IL27 and the decrease in the secretion of pro-fibrotic cytokines, IGFBP2, IL1\u03b2, IL6, IL18, PDGF, TNF\u03b1, and HGF, by irradiated HUBFs, conditioned with MSC-EVs or MSC-CM. The secretome of MSC (MSC-CM) or its subsecretome (MSC-EVs) are proangiogenic, with the ability to induce vessels from HUVEC cells, ensuring the management of bladder vascular lesions induced by irradiation. Conclusion: MSC-EVs and MSC-CM appear to have promising therapeutic potential in the prevention of RC in vitro, by targeting the three main stages of RC: fibrosis, inflammation and vascular damage.<\/jats:p>","DOI":"10.3390\/biology11070980","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T23:59:22Z","timestamp":1656460762000},"page":"980","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Two New Potential Therapeutic Approaches in Radiation Cystitis Derived from Mesenchymal Stem Cells: Extracellular Vesicles and Conditioned Medium"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7774-349X","authenticated-orcid":false,"given":"Carole","family":"Helissey","sequence":"first","affiliation":[{"name":"Clinical Unit Research, HIA B\u00e9gin, 94160 Saint-Mand\u00e9, France"},{"name":"Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Guitard","sequence":"additional","affiliation":[{"name":"Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Th\u00e9ry","sequence":"additional","affiliation":[{"name":"Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-3498","authenticated-orcid":false,"given":"Sylvie","family":"Goulinet","sequence":"additional","affiliation":[{"name":"Technical Platform iVEs, UMRS-MD 1197 (INSERM), Paul Brousse Hospital, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-1891","authenticated-orcid":false,"given":"Philippe","family":"Mauduit","sequence":"additional","affiliation":[{"name":"Technical Platform iVEs, UMRS-MD 1197 (INSERM), Paul Brousse Hospital, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Girleanu","sequence":"additional","affiliation":[{"name":"Imaging Unit, Department of Platforms and Technological Research, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Laure","family":"Favier","sequence":"additional","affiliation":[{"name":"Imaging Unit, Department of Platforms and Technological Research, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Drouet","sequence":"additional","affiliation":[{"name":"Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7346-5883","authenticated-orcid":false,"given":"Charles","family":"Parnot","sequence":"additional","affiliation":[{"name":"Cureety, 33 rue de l\u2019Amiraut\u00e9, 22100 Dinan, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0119-3695","authenticated-orcid":false,"given":"Cyrus","family":"Chargari","sequence":"additional","affiliation":[{"name":"Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"},{"name":"Department of Radiation Oncology, Gustave Roussy Comprehensive Cancer Center, 94800 Villejuif, France"},{"name":"INSERM U1030, Universit\u00e9 Paris Saclay, 94043 Le Kremlin Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Cavallero","sequence":"additional","affiliation":[{"name":"Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Fran\u00e7ois","sequence":"additional","affiliation":[{"name":"Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, 91220 Br\u00e9tigny-sur-Orge, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Helissey, C., Cavallero, S., Brossard, C., Dusaud, M., Chargari, C., and Fran\u00e7ois, S. (2020). Chronic Inflammation and Radiation-Induced Cystitis: Molecular Background and Therapeutic Perspectives. Cells, 10.","DOI":"10.3390\/cells10010021"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/0360-3016(94)00431-J","article-title":"The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy","volume":"31","author":"Marks","year":"1995","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.ijrobp.2018.02.004","article-title":"Risk of Late Urinary Complications Following Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: Refining Bladder Dose-Volume Parameters","volume":"101","author":"Manea","year":"2018","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/nau.23897","article-title":"The International Continence Society (ICS) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction","volume":"38","author":"Haylen","year":"2019","journal-title":"Neurourol. Urodyn."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.stem.2017.07.011","article-title":"Mesenchymal Stem Cells in Fibrotic Disease","volume":"21","author":"Kramann","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5173732","DOI":"10.1155\/2017\/5173732","article-title":"Mesenchymal Stem and Progenitor Cells in Regeneration: Tissue Specificity and Regenerative Potential","volume":"2017","author":"Rohban","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"36","DOI":"10.7150\/ijms.21666","article-title":"Ethical and Safety Issues of Stem Cell-Based Therapy","volume":"15","author":"Volarevic","year":"2018","journal-title":"Int. J. Med. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"B\u00f6rger, V., Bremer, M., Ferrer-Tur, R., Gockeln, L., Stambouli, O., Becic, A., and Giebel, B. (2017). M9esenchymal Stem\/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071450"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/HP.0000000000001264","article-title":"MSC-Derived Extracellular Vesicles: New Emergency Treatment to Limit the Development of Radiation-Induced Hematopoietic Syndrome?","volume":"119","author":"Cavallero","year":"2020","journal-title":"Health Phys."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tsiapalis, D., and O\u2019Driscoll, L. (2020). Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications. Cells, 9.","DOI":"10.3390\/cells9040991"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.3389\/fimmu.2018.02837","article-title":"Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning","volume":"9","author":"Ferreira","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2019.04.002","article-title":"The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine","volume":"46","author":"Kumar","year":"2019","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.jcyt.2019.08.002","article-title":"Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT\u00ae) Mesenchymal Stromal Cell committee position statement on nomenclature","volume":"21","author":"Viswanathan","year":"2019","journal-title":"Cytotherapy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1080\/14653240500319234","article-title":"Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement","volume":"7","author":"Horwitz","year":"2005","journal-title":"Cytotherapy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.radonc.2013.08.029","article-title":"Independent prospective validation of a predictive test for risk of radiation induced fibrosis based on the gene expression pattern in fibroblasts irradiated in vitro","volume":"108","author":"Andreassen","year":"2013","journal-title":"Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol."},{"key":"ref_16","first-page":"568","article-title":"Management of radiation cystitis","volume":"14","author":"Rigaud","year":"2004","journal-title":"Prog. Urol. J. L\u2019assoc. Fr. D\u2019urol. Soc. Fr. D\u2019urol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1097\/COC.0000000000000016","article-title":"Hemorrhagic radiation cystitis","volume":"38","author":"Mendenhall","year":"2015","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41586-020-2938-9","article-title":"Fibrosis: From mechanisms to medicines","volume":"587","author":"Henderson","year":"2020","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5646","DOI":"10.1210\/en.2004-0436","article-title":"Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1: Implications for diabetic nephropathy","volume":"145","author":"McLennan","year":"2004","journal-title":"Endocrinology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K","article-title":"Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model","volume":"181","author":"Mori","year":"1999","journal-title":"J. Cell. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF-\u03b2: The master regulator of fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41584-019-0322-7","article-title":"Shared and distinct mechanisms of fibrosis","volume":"15","author":"Distler","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.matbio.2015.03.005","article-title":"The role of TIMPs in regulation of extracellular matrix proteolysis","volume":"44","author":"Arpino","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"djw339","DOI":"10.1093\/jnci\/djw339","article-title":"Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis","volume":"109","author":"Bickelhaupt","year":"2017","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1084\/jem.20171491","article-title":"Human monocytes and macrophages regulate immune tolerance via integrin \u03b1v\u03b28-mediated TGF\u03b2 activation","volume":"215","author":"Kelly","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12215","DOI":"10.1073\/pnas.92.26.12215","article-title":"Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated","volume":"92","author":"Diebold","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1136\/thx.36.9.645","article-title":"Immunohistochemical study of collagen types in human foetal lung and fibrotic lung disease","volume":"36","author":"Bateman","year":"1981","journal-title":"Thorax"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/j.1365-2559.2005.02103.x","article-title":"Collagen and elastic system in the remodelling process of major types of idiopathic interstitial pneumonias (IIP)","volume":"46","author":"Rozin","year":"2005","journal-title":"Histopathology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1007\/s00345-018-2247-1","article-title":"Mesenchymal stem cells inhibit hypoxia-induced inflammatory and fibrotic pathways in bladder smooth muscle cells","volume":"36","author":"Wiafe","year":"2018","journal-title":"World J. Urol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"764641","DOI":"10.1155\/2015\/764641","article-title":"Fibrosis Related Inflammatory Mediators: Role of the IL-10 Cytokine Family","volume":"2015","author":"Sziksz","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1089\/wound.2019.1032","article-title":"The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis","volume":"9","author":"Steen","year":"2020","journal-title":"Adv. Wound Care"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12964-019-0474-8","article-title":"Bystander effects of ionizing radiation: Conditioned media from X-ray irradiated MCF-7 cells increases the angiogenic ability of endothelial cells","volume":"17","author":"Jabbari","year":"2019","journal-title":"Cell Commun. Signal. CCS"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107347","DOI":"10.1016\/j.intimp.2020.107347","article-title":"Coenzyme Q10 attenuates inflammation and fibrosis implicated in radiation enteropathy through suppression of NF-kB\/TGF-\u03b2\/MMP-9 pathways","volume":"92","author":"Mohamed","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","first-page":"5239","article-title":"Dynamic features of liver fibrogenesis and fibrosis resolution in the absence of matrix metalloproteinase-9","volume":"20","author":"Wang","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zwaans, B.M.M., Nicolai, H.E., Chancellor, M.B., and Lamb, L.E. (2020). Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0241388"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e3679047","DOI":"10.1155\/2016\/3679047","article-title":"The Therapeutic Effect of Adipose-Derived Mesenchymal Stem Cells for Radiation-Induced Bladder Injury","volume":"2016","author":"Qiu","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/s41467-020-14344-7","article-title":"Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis","volume":"11","author":"Dinh","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.3389\/fimmu.2018.02538","article-title":"Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Dendritic Cell Maturation and Function","volume":"9","author":"Reis","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev-cellbio-101512-122326","article-title":"Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles","volume":"30","author":"Colombo","year":"2014","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1093\/ndt\/gfs168","article-title":"Therapeutic potential of mesenchymal stem cell-derived microvesicles","volume":"27","author":"Biancone","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"F1626","DOI":"10.1152\/ajprenal.00339.2006","article-title":"Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury","volume":"292","author":"Weiss","year":"2007","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"531","DOI":"10.2174\/1574888X12666170522114307","article-title":"Hair Regeneration Therapy: Application of Adipose-Derived Stem Cells","volume":"12","author":"Fukuoka","year":"2017","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"519126","DOI":"10.1155\/2013\/519126","article-title":"The effect of conditioned media of adipose-derived stem cells on wound healing after ablative fractional carbon dioxide laser resurfacing","volume":"2013","author":"Zhou","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"18019","DOI":"10.1038\/s41598-017-18144-w","article-title":"Mesenchymal Stem Cell-Conditioned Medium Reduces Disease Severity and Immune Responses in Inflammatory Arthritis","volume":"7","author":"Kay","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/cns.12759","article-title":"Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy","volume":"23","author":"Dahbour","year":"2017","journal-title":"CNS Neurosci. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sagaradze, G., Grigorieva, O., Nimiritsky, P., Basalova, N., Kalinina, N., Akopyan, Z., and Efimenko, A. (2019). Conditioned Medium from Human Mesenchymal Stromal Cells: Towards the Clinical Translation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071656"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Tutuianu, R., Rosca, A.-M., Iacomi, D.M., Simionescu, M., and Titorencu, I. (2021). Human Mesenchymal Stromal Cell-Derived Exosomes Promote In Vitro Wound Healing by Modulating the Biological Properties of Skin Keratinocytes and Fibroblasts and Stimulating Angiogenesis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126239"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/2045-3701-1-14","article-title":"Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: Involvement of hepatocyte STAT3 in TIMP-1 production","volume":"1","author":"TWang","year":"2011","journal-title":"Cell Biosci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Basalova, N., Sagaradze, G., Arbatskiy, M., Evtushenko, E., Kulebyakin, K., Grigorieva, O., Akopyan, Z., Kalinina, N., and Efimenko, A. (2020). Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles. Cells, 9.","DOI":"10.3390\/cells9051272"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and molecular mechanisms of fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chiahsuan, C., Lee, J., Ravichandran, R., Fleming, T., Wheatcroft, S., Kearney, M., Bremner, R., Mohanakumar, T., Flint, D.J., and Sureshbabu, A. (2021, January 21). IGFBP2 Protects against Pulmonary Fibrosis through Inhibiting P21-Mediated Senescence. Available online: https:\/\/www.biorxiv.org\/content\/10.1101\/2021.01.21.427684v1.","DOI":"10.1101\/2021.01.21.427684"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"120525","DOI":"10.1155\/2014\/120525","article-title":"The role(s) of cytokines\/chemokines in urinary bladder inflammation and dysfunction","volume":"2014","author":"Gonzalez","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.4049\/jimmunol.170.6.3369","article-title":"IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis","volume":"170","author":"Li","year":"2003","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1182\/blood.V96.1.34","article-title":"Human endothelial cells express CCR2 and respond to MCP-1: Direct role of MCP-1 in angiogenesis and tumor progression","volume":"96","author":"Salcedo","year":"2000","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"PMC3701743","DOI":"10.1002\/art.37981","article-title":"Evidence for CXCL16 as a potent angiogenic mediator and endothelial progenitor cell chemotactic factor","volume":"65","author":"Isozaki","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_56","unstructured":"Abdullah, M. (2021, January 21). Effectiveness and Safety Profile of Mesenchymal Stem Cell Secretomes as a Treatment for Severe Cases of COVID-19, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05122234."},{"key":"ref_57","unstructured":"Putra, A. (2021, January 21). The Effect of Secretome of Hypoxia-Mesenchymal Stem Cells in Improving Survival of Severe COVID-19 Patients, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04753476."},{"key":"ref_58","unstructured":"Avicenna Research Institute (2021, January 21). Safety and Efficacy Study of Allogeneic Human Menstrual Blood Stem Cells Secretome to Treat Severe COVID-19 Patients, Clinical Trial Phase I&II, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05019287."},{"key":"ref_59","unstructured":"PT. Prodia Stem Cell Indonesia (2021, January 21). Safety and Efficacy of Combined Conditioned Medium with Umbilical Cord Mesenchymal Stem Cells as a Novel Strategy for Sub-Acute Stroke Infarct, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05008588."},{"key":"ref_60","unstructured":"Direct Biologics, LLC (2021, January 21). Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion Treatment for Acute Respiratory Distress Syndrome: A Phase I\/II Clinical Trial, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05127122."},{"key":"ref_61","unstructured":"Direct Biologics, LLC (2021, January 21). Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion Treatment for Mild-to-Moderate COVID-19: A Phase II Clinical Trial, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05125562."},{"key":"ref_62","unstructured":"Direct Biologics, LLC (2021, January 21). Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion Treatment: Expanded Access Protocol for Patients With COVID-19 Associated ARDS Who Do Not Qualify for Phase II Randomized Control Trial, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04657458."},{"key":"ref_63","unstructured":"Direct Biologics, LLC (2021, January 21). A Phase I Study of ExoFlo, an ex Vivo Culture-expanded Adult Allogeneic Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicle Isolate Product, for the Treatment of Medically Refractory Crohn\u2019s Disease, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05130983."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/7\/980\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:47Z","timestamp":1760139587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/7\/980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,28]]},"references-count":63,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["biology11070980"],"URL":"https:\/\/doi.org\/10.3390\/biology11070980","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,28]]}}}