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Recent evidence suggests that the therapeutic benefits of MSCs do not depend directly on their ability to proliferate but rather on their capacity to release extracellular nanovesicles known as exosomes (MSC-Exos). MSC-Exos are rich in bioactive molecules such as microRNAs, which can modulate gene expression and trigger significant biological responses, playing a central role in modulating immune responses, inhibiting fibrotic pathways and promoting tissue repair and angiogenesis. Preclinical studies have demonstrated that MSC-Exos can attenuate fibrosis, modulate macrophage polarization, suppress autoreactive lymphocyte activity, and even reverse pulmonary arterial hypertension in animal models of SSc. Compared to cell-based therapies, MSC-Exos offer several advantages, including lower immunogenicity and better safety profile. This review provides an overview of the immunomodulatory, antifibrotic, and angiogenic properties of MSC-Exos and explores their potential as novel cell-free therapy for SSc.<\/jats:p>","DOI":"10.3390\/cells14131018","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T09:57:39Z","timestamp":1751536659000},"page":"1018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mesenchymal Stem-Cell-Derived Exosomes and MicroRNAs: Advancing Cell-Free Therapy in Systemic Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Cristiano","family":"Barbetta","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, AOU Careggi, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7744-8549","authenticated-orcid":false,"given":"Francesco","family":"Bonomi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital Careggi, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Lepri","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, AOU Careggi, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Furst","sequence":"additional","affiliation":[{"name":"Southern California Scleroderma and Rheumatology Centre, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5926-6263","authenticated-orcid":false,"given":"Silvia Bellando","family":"Randone","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, AOU Careggi, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2722-6475","authenticated-orcid":false,"given":"Serena","family":"Guiducci","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, AOU Careggi, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e267","DOI":"10.1016\/j.lpm.2014.08.001","article-title":"Pathophysiology of Systemic Sclerosis: State of the Art in 2014","volume":"43","author":"Dumoitier","year":"2014","journal-title":"La Presse M\u00e9dicale"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1161\/CIRCRESAHA.111.243147","article-title":"Mesenchymal Stem Cells","volume":"109","author":"Williams","year":"2011","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.stem.2008.03.002","article-title":"Mesenchymal Stem Cells: Revisiting History, Concepts, and Assays","volume":"2","author":"Bianco","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3727\/096368915X689622","article-title":"Clinical Trials with Mesenchymal Stem Cells: An Update","volume":"25","author":"Squillaro","year":"2016","journal-title":"Cell Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1002\/stem.2575","article-title":"Concise Review: MSC-Derived Exosomes for Cell-Free Therapy","volume":"35","author":"Phinney","year":"2017","journal-title":"Stem Cells"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1186\/s13075-015-0819-7","article-title":"Update on Mesenchymal Stem Cell-Based Therapy in Lupus and Scleroderma","volume":"17","author":"Cras","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kalluri, R., and LeBleu, V.S. (2020). The Biology, Function, and Biomedical Applications of Exosomes. Science, 367.","DOI":"10.1126\/science.aau6977"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"650","DOI":"10.7326\/0003-4819-153-10-201011160-00007","article-title":"Autologous Mesenchymal Stem Cells Foster Revascularization of Ischemic Limbs in Systemic Sclerosis","volume":"153","author":"Guiducci","year":"2010","journal-title":"Ann. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"263","DOI":"10.3109\/s10165-010-0274-x","article-title":"Therapeutic Angiogenesis in Patients with Systemic Sclerosis by Autologous Transplantation of Bone-Marrow-Derived Cells","volume":"20","author":"Ishigatsubo","year":"2010","journal-title":"Mod. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.3727\/096368914X685636","article-title":"Regional Implantation of Autologous Adipose Tissue-Derived Cells Induces a Prompt Healing of Long-Lasting Indolent Digital Ulcers in Patients with Systemic Sclerosis","volume":"24","author":"Sambataro","year":"2015","journal-title":"Cell Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1253\/circj.CJ-18-1044","article-title":"Impact of Therapeutic Angiogenesis Using Autologous Bone Marrow-Derived Mononuclear Cells Implantation in Critical Limb Ischemia With Scleroderma\u2015Subanalysis of the Long-Term Clinical Outcomes Survey","volume":"83","author":"Shoji","year":"2019","journal-title":"Circ. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"48","DOI":"10.21037\/sci.2016.09.03","article-title":"Mesenchymal Stem Cell Therapy for Refractory Scleroderma: A Report of 2 Cases","volume":"3","author":"Wehbe","year":"2016","journal-title":"Stem Cell Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1038\/sj.leu.2404996","article-title":"Marked Improvement of Severe Progressive Systemic Sclerosis after Transplantation of Mesenchymal Stem Cells from an Allogeneic Haploidentical-Related Donor Mediated by Ligation of CD137L","volume":"22","author":"Christopeit","year":"2008","journal-title":"Leukemia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1093\/rheumatology\/ket432","article-title":"Therapeutic Vascular Angiogenesis for Intractable Macroangiopathy-Related Digital Ulcer in Patients with Systemic Sclerosis: A Pilot Study","volume":"53","author":"Takagi","year":"2014","journal-title":"Rheumatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1002\/art.30431","article-title":"Treatment of Severe Progressive Systemic Sclerosis with Transplantation of Mesenchymal Stromal Cells from Allogeneic Related Donors: Report of Five Cases","volume":"63","author":"Keyszer","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s13075-017-1373-2","article-title":"Sustained Benefit from Combined Plasmapheresis and Allogeneic Mesenchymal Stem Cells Transplantation Therapy in Systemic Sclerosis","volume":"19","author":"Zhang","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_17","first-page":"1014","article-title":"Efficacy of Mesenchymal Stem Cells on Systemic Lupus Erythematosus: A Meta-Analysis","volume":"50","author":"Liu","year":"2018","journal-title":"Beijing Da Xue Xue bao. Yi Xue Ban = J. Peking Univ. Health Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12967-018-1541-4","article-title":"Serum IFN-\u03b3 Levels Predict the Therapeutic Effect of Mesenchymal Stem Cell Transplantation in Active Rheumatoid Arthritis","volume":"16","author":"Yang","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102831","DOI":"10.1016\/j.autrev.2021.102831","article-title":"Human Mesenchymal Stem Cells for the Management of Systemic Sclerosis. Systematic Review","volume":"20","author":"Aguilera","year":"2021","journal-title":"Autoimmun. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Welsh, J.A., Goberdhan, D.C.I., O\u2019Driscoll, L., Buzas, E.I., Blenkiron, C., Bussolati, B., Cai, H., Di Vizio, D., Driedonks, T.A.P., and Erdbr\u00fcgger, U. (2024). Minimal Information for Studies of Extracellular Vesicles (MISEV2023): From Basic to Advanced Approaches. J. Extracell. Vesicles, 13.","DOI":"10.1002\/jev2.12451"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hunter, M.P., Ismail, N., Zhang, X., Aguda, B.D., Lee, E.J., Yu, L., Xiao, T., Schafer, J., Lee, M.-L.T., and Schmittgen, T.D. (2008). Detection of MicroRNA Expression in Human Peripheral Blood Microvesicles. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003694"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12964-015-0124-8","article-title":"MSC Surface Markers (CD44, CD73, and CD90) Can Identify Human MSC-Derived Extracellular Vesicles by Conventional Flow Cytometry","volume":"14","author":"Ramos","year":"2016","journal-title":"Cell Commun. Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E968","DOI":"10.1073\/pnas.1521230113","article-title":"Proteomic Comparison Defines Novel Markers to Characterize Heterogeneous Populations of Extracellular Vesicle Subtypes","volume":"113","author":"Kowal","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Almeria, C., Weiss, R., Roy, M., Tripisciano, C., Kasper, C., Weber, V., and Egger, D. (2019). Hypoxia Conditioned Mesenchymal Stem Cell-Derived Extracellular Vesicles Induce Increased Vascular Tube Formation in Vitro. Front. Bioeng. Biotechnol., 7.","DOI":"10.3389\/fbioe.2019.00292"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s13770-021-00405-5","article-title":"The Therapeutic Effects of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells on Scleroderma","volume":"19","author":"Yu","year":"2022","journal-title":"Tissue Eng. Regen. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1089\/scd.2018.0015","article-title":"Human Fetal Liver Mesenchymal Stem Cell-Derived Exosomes Impair Natural Killer Cell Function","volume":"28","author":"Fan","year":"2019","journal-title":"Stem Cells Dev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Reis, M., Mavin, E., Nicholson, L., Green, K., Dickinson, A.M., and Wang, X. (2018). Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Dendritic Cell Maturation and Function. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02538"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Adamo, A., Brandi, J., Caligola, S., Delfino, P., Bazzoni, R., Carusone, R., Cecconi, D., Giugno, R., Manfredi, M., and Robotti, E. (2019). Extracellular Vesicles Mediate Mesenchymal Stromal Cell-Dependent Regulation of B Cell PI3K-AKT Signaling Pathway and Actin Cytoskeleton. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00446"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1002\/stem.2759","article-title":"Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal\/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations","volume":"36","author":"Fujii","year":"2018","journal-title":"Stem Cells"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1177\/0963689718805375","article-title":"Exosomes Derived from IDO1-Overexpressing Rat Bone Marrow Mesenchymal Stem Cells Promote Immunotolerance of Cardiac Allografts","volume":"27","author":"He","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1002\/stem.1934","article-title":"Bone Marrow-Derived Mesenchymal Stromal Cells Harness Purinergenic Signaling to Tolerize Human Th1 Cells In Vivo","volume":"33","author":"Amarnath","year":"2015","journal-title":"Stem Cells"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1080\/08820139.2022.2090261","article-title":"Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Diffuse Alveolar Hemorrhage Associated with Systemic Lupus Erythematosus in Mice by Promoting M2 Macrophage Polarization via the MicroRNA-146a-5p\/NOTCH1 Axis","volume":"51","author":"Chen","year":"2022","journal-title":"Immunol. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.intimp.2019.04.020","article-title":"Extracellular Vesicles Derived from Bone Marrow Mesenchymal Stem Cells Attenuate Dextran Sodium Sulfate-Induced Ulcerative Colitis by Promoting M2 Macrophage Polarization","volume":"72","author":"Cao","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Xing, Y., Li, B., He, J., and Hua, H. (2022). Labial Gland Mesenchymal Stem Cell Derived Exosomes-Mediated MiRNA-125b Attenuates Experimental Sjogren\u2019s Syndrome by Targeting PRDM1 and Suppressing Plasma Cells. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.871096"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1186\/s13287-021-02541-0","article-title":"Labial Gland-Derived Mesenchymal Stem Cells and Their Exosomes Ameliorate Murine Sj\u00f6gren\u2019s Syndrome by Modulating the Balance of Treg and Th17 Cells","volume":"12","author":"Li","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.intimp.2018.12.001","article-title":"Exosomes Derived from Mesenchymal Stem Cells Attenuate Inflammation and Demyelination of the Central Nervous System in EAE Rats by Regulating the Polarization of Microglia","volume":"67","author":"Li","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3727\/096368915X688173","article-title":"Infusion of Human Bone Marrow-Derived Mesenchymal Stem Cells Alleviates Autoimmune Nephritis in a Lupus Model by Suppressing Follicular Helper T-Cell Development","volume":"25","author":"Jang","year":"2016","journal-title":"Cell Transplant."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9433","DOI":"10.1002\/jcb.27260","article-title":"Immunomodulatory Effects of Mesenchymal Stem Cell-Derived Exosomes on Experimental Type-1 Autoimmune Diabetes","volume":"119","author":"Nojehdehi","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"20310","DOI":"10.1002\/jcp.28631","article-title":"Potential of Stem Cell-derived Exosomes to Regenerate \u03b2 Islets through Pdx-1 Dependent Mechanism in a Rat Model of Type 1 Diabetes","volume":"234","author":"Mahdipour","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_41","first-page":"132","article-title":"MiR-205-5p in Exosomes Divided from Chondrogenic Mesenchymal Stem Cells Alleviated Rheumatoid Arthritis via Regulating MDM2 in Fibroblast-like Synoviocytes","volume":"22","author":"Ma","year":"2022","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.4049\/jimmunol.1800304","article-title":"Therapeutic Potential of Mesenchymal Cell\u2013Derived MiRNA-150-5p\u2013Expressing Exosomes in Rheumatoid Arthritis Mediated by the Modulation of MMP14 and VEGF","volume":"201","author":"Chen","year":"2018","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Meng, Q., and Qiu, B. (2020). Exosomal MicroRNA-320a Derived From Mesenchymal Stem Cells Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Activation by Suppressing CXCL9 Expression. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00441"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111365","DOI":"10.1016\/j.intimp.2023.111365","article-title":"Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Loaded MiR-451a Targets ATF2 to Improve Rheumatoid Arthritis","volume":"127","author":"Mi","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1089\/jir.2021.0146","article-title":"Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Psoriasis-like Skin Inflammation","volume":"42","author":"Zhang","year":"2022","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.stemcr.2017.04.008","article-title":"MSC-Derived Extracellular Vesicles Attenuate Immune Responses in Two Autoimmune Murine Models: Type 1 Diabetes and Uveoretinitis","volume":"8","author":"Oh","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wang, G., Yuan, J., Cai, X., Xu, Z., Wang, J., Ocansey, D.K.W., Yan, Y., Qian, H., Zhang, X., and Xu, W. (2020). HucMSC-exosomes Carrying MiR-326 Inhibit Neddylation to Relieve Inflammatory Bowel Disease in Mice. Clin. Transl. Med., 10.","DOI":"10.1002\/ctm2.113"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1186\/s13287-021-02400-y","article-title":"BMSC-Derived Extracellular Vesicles Intervened the Pathogenic Changes of Scleroderma in Mice through MiRNAs","volume":"12","author":"Jin","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"102660","DOI":"10.1016\/j.jaut.2021.102660","article-title":"Mesenchymal Stromal Cells-Derived Extracellular Vesicles Alleviate Systemic Sclerosis via MiR-29a-3p","volume":"121","author":"Rozier","year":"2021","journal-title":"J. Autoimmun."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Xiao, Y., Xiang, Q., Wang, Y., Huang, Z., Yang, J., Zhang, X., Zhu, X., Xue, Y., Wan, W., and Zou, H. (2025). Exosomes Carrying Adipose Mesenchymal Stem Cells Function Alleviate Scleroderma Skin Fibrosis by Inhibiting the TGF-\u03921\/Smad3 Axis. Sci. Rep., 15.","DOI":"10.1038\/s41598-024-72630-6"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.molimm.2023.03.017","article-title":"Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Alleviate Skin Fibrosis in Systemic Sclerosis by Inhibiting the IL-33\/ST2 Axis via the Delivery of MicroRNA-214","volume":"157","author":"Xie","year":"2023","journal-title":"Mol. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/cr.2017.11","article-title":"Mesenchymal Stem Cell Transplantation in Tight-Skin Mice Identifies MiR-151-5p as a Therapeutic Target for Systemic Sclerosis","volume":"27","author":"Chen","year":"2017","journal-title":"Cell Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Rozier, P., Maumus, M., Bony, C., Maria, A.T.J., Sabatier, F., Jorgensen, C., Guilpain, P., and No\u00ebl, D. (2021). Extracellular Vesicles Are More Potent Than Adipose Mesenchymal Stromal Cells to Exert an Anti-Fibrotic Effect in an In Vitro Model of Systemic Sclerosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136837"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/cei.13599","article-title":"Endothelial-to-Mesenchymal Transition in Systemic Sclerosis","volume":"205","author":"Ruscitti","year":"2021","journal-title":"Clin. Exp. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1101\/gr.132514.111","article-title":"Impact of MicroRNA Regulation on Variation in Human Gene Expression","volume":"22","author":"Lu","year":"2012","journal-title":"Genome Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Collares, C.V., Evangelista, A.F., Xavier, D.J., Rassi, D.M., Arns, T., Foss-Freitas, M.C., Foss, M.C., Puthier, D., Sakamoto-Hojo, E.T., and Passos, G.A. (2013). Identifying Common and Specific MicroRNAs Expressed in Peripheral Blood Mononuclear Cell of Type 1, Type 2, and Gestational Diabetes Mellitus Patients. BMC Res. Notes, 6.","DOI":"10.1186\/1756-0500-6-491"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"\u00c5kerman, L., Casas, R., Ludvigsson, J., Tavira, B., and Skoglund, C. (2018). Serum MiRNA Levels Are Related to Glucose Homeostasis and Islet Autoantibodies in Children with High Risk for Type 1 Diabetes. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191067"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1177\/0961203319829853","article-title":"Downregulation of MiR-633 Activated AKT\/MTOR Pathway by Targeting AKT1 in Lupus CD4+ T Cells","volume":"28","author":"Chen","year":"2019","journal-title":"Lupus"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1159\/000485987","article-title":"MiRNA and MRNA Profiling in Systemic Lupus Reveals a Novel Set of Cytokine-Related MiRNAs and Their Target Genes in Cases With and Without Renal Involvement","volume":"42","author":"Arda","year":"2017","journal-title":"Kidney Blood Press. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1186\/s12967-018-1739-5","article-title":"NovelmiRNA-25 Inhibits AMPD2 in Peripheral Blood Mononuclear Cells of Patients with Systemic Lupus Erythematosus and Represents a Promising Novel Biomarker","volume":"16","author":"Guo","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"12446","DOI":"10.1074\/jbc.M114.550723","article-title":"MiR-17-92 Cluster Targets Phosphatase and Tensin Homology and Ikaros Family Zinc Finger 4 to Promote TH17-Mediated Inflammation","volume":"289","author":"Liu","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Venkatesha, S.H., Dudics, S., Song, Y., Mahurkar, A., and Moudgil, K.D. (2018). The MiRNA Expression Profile of Experimental Autoimmune Encephalomyelitis Reveals Novel Potential Disease Biomarkers. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123990"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1002\/art.40163","article-title":"Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis","volume":"69","author":"Rossato","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"595","DOI":"10.3109\/14397595.2014.1001311","article-title":"MicroRNA-130b Regulates Scleroderma Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor \u03b3","volume":"25","author":"Luo","year":"2015","journal-title":"Mod. Rheumatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jaut.2017.12.015","article-title":"Serum MicroRNA Screening and Functional Studies Reveal MiR-483-5p as a Potential Driver of Fibrosis in Systemic Sclerosis","volume":"89","author":"Chouri","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13075-017-1331-z","article-title":"Mir-155 Is Overexpressed in Systemic Sclerosis Fibroblasts and Is Required for NLRP3 Inflammasome-Mediated Collagen Synthesis during Fibrosis","volume":"19","author":"Artlett","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.biopha.2016.12.080","article-title":"MicroRNA-202-3p Regulates Scleroderma Fibrosis by Targeting Matrix Metalloproteinase 1","volume":"87","author":"Zhou","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1021\/pr200682z","article-title":"Proteomic Analysis of Microvesicles Derived from Human Mesenchymal Stem Cells","volume":"11","author":"Kim","year":"2012","journal-title":"J. Proteome. Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Ferguson, S.W., Wang, J., Lee, C.J., Liu, M., Neelamegham, S., Canty, J.M., and Nguyen, J. (2018). The MicroRNA Regulatory Landscape of MSC-Derived Exosomes: A Systems View. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-19581-x"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.5966\/sctm.2015-0367","article-title":"Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-\u03b2\/SMAD2 Pathway During Wound Healing","volume":"5","author":"Fang","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jdermsci.2021.08.006","article-title":"Antifibrotic Effects and Mechanisms of Mesenchymal Stem Cell-Derived Exosomes in a Systemic Sclerosis Mouse Model: Possible Contribution of MiR-196b-5p","volume":"104","author":"Baral","year":"2021","journal-title":"J. Dermatol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1080\/14397595.2020.1859726","article-title":"Serum Protein Levels of YKL-40 and Plasma MiR-214 Expression in Patients with Systemic Sclerosis","volume":"31","author":"Dichev","year":"2021","journal-title":"Mod. Rheumatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"110","DOI":"10.4070\/kcj.2021.0191","article-title":"Stem Cell and Exosome Therapy in Pulmonary Hypertension","volume":"52","author":"Oh","year":"2022","journal-title":"Korean Circ. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1161\/CIRCULATIONAHA.112.114173","article-title":"Exosomes Mediate the Cytoprotective Action of Mesenchymal Stromal Cells on Hypoxia-Induced Pulmonary Hypertension","volume":"126","author":"Lee","year":"2012","journal-title":"Circulation"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12931-020-1331-4","article-title":"Mesenchymal Stromal Cell-Derived Exosomes Improve Pulmonary Hypertension through Inhibition of Pulmonary Vascular Remodeling","volume":"21","author":"Zhang","year":"2020","journal-title":"Respir. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1093\/cvr\/cvw054","article-title":"Exosomes Induce and Reverse Monocrotaline-Induced Pulmonary Hypertension in Mice","volume":"110","author":"Aliotta","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1007\/s10067-022-06446-y","article-title":"Pulmonary Hypertension in Connective Tissue Diseases: Epidemiology, Pathogenesis, and Treatment","volume":"42","author":"Cansu","year":"2023","journal-title":"Clin. Rheumatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"10","DOI":"10.2174\/1574889810666150702124059","article-title":"Exosome-Based Strategies for Diagnosis and Therapy","volume":"10","author":"Urbanelli","year":"2015","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Chakr, R., Pavan, T., Siqueira, I., Zanchet, D., Calegaro, N., Andrade, N., Neto, G., Neves, M., Bredemeier, M., and Palominos, P. (2013). AB0505\u2005Case Report of Allogeneic Unrelated-Donor Mesenchymal Stem Cells (Msc) Infusion in Systemic Sclerosis (Ssc). Ann. Rheum. Dis., 72.","DOI":"10.1136\/annrheumdis-2013-eular.2827"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.mvr.2009.02.001","article-title":"Is the Intravascular Administration of Mesenchymal Stem Cells Safe?","volume":"77","author":"Furlani","year":"2009","journal-title":"Microvasc. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1161\/CIRCRESAHA.110.239848","article-title":"Malignant Tumor Formation After Transplantation of Short-Term Cultured Bone Marrow Mesenchymal Stem Cells in Experimental Myocardial Infarction and Diabetic Neuropathy","volume":"108","author":"Jeong","year":"2011","journal-title":"Circ. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1111\/cas.14563","article-title":"Biology and Therapeutic Potential of Mesenchymal Stem Cell-derived Exosomes","volume":"111","author":"Xunian","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Mendt, M., Kamerkar, S., Sugimoto, H., McAndrews, K.M., Wu, C.-C., Gagea, M., Yang, S., Blanko, E.V.R., Peng, Q., and Ma, X. (2018). Generation and Testing of Clinical-Grade Exosomes for Pancreatic Cancer. JCI Insight, 3.","DOI":"10.1172\/jci.insight.99263"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1479-5876-9-86","article-title":"Body Fluid Derived Exosomes as a Novel Template for Clinical Diagnostics","volume":"9","author":"Keller","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Nassar, W., El-Ansary, M., Sabry, D., Mostafa, M.A., Fayad, T., Kotb, E., Temraz, M., Saad, A.-N., Essa, W., and Adel, H. (2016). Umbilical Cord Mesenchymal Stem Cells Derived Extracellular Vesicles Can Safely Ameliorate the Progression of Chronic Kidney Diseases. Biomater. Res., 20.","DOI":"10.1186\/s40824-016-0068-0"},{"key":"ref_86","first-page":"101923","article-title":"Improvement in the Clinical Manifestations of Interstitial Lung Disease Following Treatment with Placental Mesenchymal Stromal Cell Extracellular Vesicles in a Patient with Systemic Sclerosis: A Case Report","volume":"46","author":"Assar","year":"2023","journal-title":"Respir. Med. Case Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1073\/pnas.1522297113","article-title":"Chromatographically Isolated CD63+ CD81+ Extracellular Vesicles from Mesenchymal Stromal Cells Rescue Cognitive Impairments after TBI","volume":"113","author":"Kim","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"14888","DOI":"10.1073\/pnas.1408301111","article-title":"Quantitative and Stoichiometric Analysis of the MicroRNA Content of Exosomes","volume":"111","author":"Chevillet","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1021\/nn404945r","article-title":"Dynamic Biodistribution of Extracellular Vesicles in Vivo Using a Multimodal Imaging Reporter","volume":"8","author":"Lai","year":"2014","journal-title":"ACS Nano"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"30081","DOI":"10.1021\/acsami.8b08449","article-title":"Enhanced Therapeutic Effects of Mesenchymal Stem Cell-Derived Exosomes with an Injectable Hydrogel for Hindlimb Ischemia Treatment","volume":"10","author":"Zhang","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13287-020-02061-3","article-title":"Combination of Lyophilized Adipose-Derived Stem Cell Concentrated Conditioned Medium and Polysaccharide Hydrogel in the Inhibition of Hypertrophic Scarring","volume":"12","author":"Zhang","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Rozier, P., Maumus, M., Maria, A.T.J., Toupet, K., Jorgensen, C., Guilpain, P., and No\u00ebl, D. (2021). Lung Fibrosis Is Improved by Extracellular Vesicles from IFN\u03b3-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis. Cells, 10.","DOI":"10.3390\/cells10102727"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"You, D.G., Lim, G.T., Kwon, S., Um, W., Oh, B.H., Song, S.H., Lee, J., Jo, D.-G., Cho, Y.W., and Park, J.H. (2021). Metabolically Engineered Stem Cell\u2013Derived Exosomes to Regulate Macrophage Heterogeneity in Rheumatoid Arthritis. Sci. Adv., 7.","DOI":"10.1126\/sciadv.abe0083"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Fang, T., Li, B., Li, M., Zhang, Y., Jing, Z., Li, Y., Xue, T., Zhang, Z., Fang, W., and Lin, Z. (2023). Engineered Cell Membrane Vesicles Expressing CD40 Alleviate System Lupus Nephritis by Intervening B Cell Activation. 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