{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:09Z","timestamp":1787027829843,"version":"build-2736575974"},"reference-count":79,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T00:00:00Z","timestamp":1555977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente"],"award-info":[{"award-number":["Ricerca Corrente"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mesenchymal stem cells (MSCs) are promising tools for cell-based therapies due to their homing to injury sites, where they secrete bioactive factors such as cytokines, lipids, and nucleic acids, either free or conveyed within extracellular vesicles (EVs). Depending on the local environment, MSCs\u2019 therapeutic value may be modulated, determining their fate and cell behavior. Inflammatory signals may induce critical changes on both the phenotype and secretory portfolio. Intriguingly, in animal models resembling joint diseases as osteoarthritis (OA), inflammatory priming enhanced the healing capacity of MSC-derived EVs. In this work, we selected miRNA reference genes (RGs) from the literature (let-7a-5p, miR-16-5p, miR-23a-3p, miR-26a-5p, miR-101-3p, miR-103a-3p, miR-221-3p, miR-423-5p, miR-425-5p, U6 snRNA), using EVs isolated from adipose-derived MSCs (ASCs) primed with IFN\u03b3 (iASCs). geNorm, NormFinder, BestKeeper, and \u0394Ct methods identified miR-26a-5p\/16-5p as the most stable, while miR-103a-rp\/425-5p performed poorly. Our results were validated on miRNAs involved in OA cartilage trophism. Only a proper normalization strategy reliably identified the differences between donors, a critical factor to empower the therapeutic value of future off-the-shelf MSC-EV isolates. In conclusion, the proposed pipeline increases the accuracy of MSC-EVs embedded miRNAs assessment, and help predicting donor variability for precision medicine approaches.<\/jats:p>","DOI":"10.3390\/cells8040369","type":"journal-article","created":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T03:14:28Z","timestamp":1556075668000},"page":"369","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Insights into Inflammatory Priming of Adipose-Derived Mesenchymal Stem Cells: Validation of Extracellular Vesicles-Embedded miRNA Reference Genes as A Crucial Step for Donor Selection"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0272-7417","authenticated-orcid":false,"given":"Enrico","family":"Ragni","sequence":"first","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"De Luca","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Perucca Orfei","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1800-3424","authenticated-orcid":false,"given":"Alessandra","family":"Colombini","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6463-6564","authenticated-orcid":false,"given":"Marco","family":"Vigan\u00f2","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3068-7339","authenticated-orcid":false,"given":"Gaia","family":"Lugano","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0370-9598","authenticated-orcid":false,"given":"Valentina","family":"Bollati","sequence":"additional","affiliation":[{"name":"EPIGET\u2014Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, University of Milan, I-20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"de Girolamo","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Istituto Ortopedico Galeazzi, I-20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2217\/rme.14.73","article-title":"The translation of cell-based therapies: Clinical landscape and manufacturing challenges","volume":"10","author":"Heathman","year":"2015","journal-title":"Regen. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Fitzsimmons, R.E.B., Mazurek, M.S., Soos, A., and Simmons, C.A. (2018). Mesenchymal Stromal\/Stem Cells in Regenerative Medicine and Tissue Engineering. Stem Cells Int., 18.","DOI":"10.1155\/2018\/8031718"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Vizoso, F.J., Eiro, N., Cid, S., Schneider, J., and Perez-Fernandez, R. (2017). Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091852"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/sctm.17-0051","article-title":"Mesenchymal Stem Cells: Time to Change the Name!","volume":"6","author":"Caplan","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.3109\/07388551.2015.1084266","article-title":"Human cell lines for biopharmaceutical manufacturing: History, status, and future perspectives","volume":"36","author":"Dumont","year":"2016","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_6","first-page":"3924","article-title":"Precision manufacturing for clinical-quality regenerative medicines","volume":"370","author":"Williams","year":"2012","journal-title":"Philos. Trans. A Math. Phys. Eng. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2217\/rme.11.105","article-title":"Developing assays to address identity, potency, purity and safety: Cell characterization in cell therapy process development","volume":"7","author":"Carmen","year":"2012","journal-title":"Regen. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bej.2015.06.018","article-title":"Characterization of human mesenchymal stem cells from multiple donors and the implications for large scale bioprocess development","volume":"108","author":"Heathman","year":"2016","journal-title":"Biochem. Engin. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13287-017-0531-4","article-title":"Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro","volume":"8","author":"Cunningham","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1089\/scd.2014.0581","article-title":"Licensing by Inflammatory Cytokines Abolishes Heterogeneity of Immunosuppressive Function of Mesenchymal Stem Cell Population","volume":"24","author":"Hornung","year":"2015","journal-title":"Stem Cells Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1038\/leu.2011.108","article-title":"Mesenchymal stromal cell \u2018licensing\u2019: A multistep process","volume":"25","author":"Krampera","year":"2011","journal-title":"Leukemia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1002\/eji.200738129","article-title":"IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease","volume":"38","author":"Polchert","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1517\/14712598.2016.1093108","article-title":"Therapeutic application of mesenchymal stem cells in osteoarthritis","volume":"16","author":"Ruiz","year":"2016","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1016\/j.joca.2015.03.025","article-title":"Lack of anti-inflammatory and anti-catabolic effects on basal inflamed osteoarthritic chondrocytes or synoviocytes by adipose stem cell-conditioned medium","volume":"23","author":"Manferdini","year":"2015","journal-title":"Osteoarthritis Cartilage"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"De Luca, P., Kouroupis, D., Vigan\u00f2, M., Perucca-Orfei, C., Kaplan, L., Zagra, L., de Girolamo, L., Correa, D., and Colombini, A. (2019). Human Diseased Articular Cartilage Contains a Mesenchymal Stem Cell-Like Population of Chondroprogenitors with Strong Immunomodulatory Responses. J. Clin. Med., 8.","DOI":"10.3390\/jcm8040423"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1111\/j.1365-2249.2010.04256.x","article-title":"Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells","volume":"162","author":"Crop","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3389\/fimmu.2016.00392","article-title":"Utility of a Mouse Model of Osteoarthritis to Demonstrate Cartilage Protection by IFN\u03b3-Primed Equine Mesenchymal Stem Cells","volume":"7","author":"Maumus","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Serejo, T.R.T., Silva-Carvalho, A.\u00c9., Braga, L.D.C.F., Neves, F.A.R., Pereira, R.W., Carvalho, J.L., and Saldanha-Araujo, F. (2019). Assessment of the Immunosuppressive Potential of INF-\u03b3 Licensed Adipose Mesenchymal Stem Cells, Their Secretome and Extracellular Vesicles. Cells, 8.","DOI":"10.3390\/cells8010022"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"298","DOI":"10.22203\/eCM.v027a21","article-title":"Donor-matched mesenchymal stem cells from knee infrapatellar and subcutaneous adipose tissue of osteoarthritic donors display differential chondrogenic and osteogenic commitment","volume":"27","author":"Lopa","year":"2014","journal-title":"Eur. Cell Mater."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9321","DOI":"10.1038\/s41598-018-27587-8","article-title":"Low-affinity Nerve Growth Factor Receptor (CD271) Heterogeneous Expression in Adult and Fetal Mesenchymal Stromal Cells","volume":"8","author":"Barilani","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1002\/stem.2557","article-title":"Extracellular Vesicle-Shuttled mRNA in Mesenchymal Stem Cell Communication","volume":"35","author":"Ragni","year":"2017","journal-title":"Stem Cells"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gouin, K., Peck, K., Antes, T., Johnson, J.L., Li, C., Vaturi, S.D., Middleton, R., de Couto, G., Walravens, A.S., and Rodriguez-Borlado, L. (2017). A comprehensive method for identification of suitable reference genes in extracellular vesicles. J. Extracell. Vesicles, 6.","DOI":"10.1080\/20013078.2017.1347019"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lv, C., and Yang, T. (2018). Effective enrichment of urinary exosomes by polyethylene glycol for RNA detection. Biomed. Res., 29.","DOI":"10.4066\/biomedicalresearch.29-17-1695"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"893594","DOI":"10.1155\/2015\/893594","article-title":"Identification of endogenous controls for analyzing serum exosomal miRNA in patients with hepatitis B or hepatocellular carcinoma","volume":"2015","author":"Li","year":"2015","journal-title":"Dis. Markers"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.healun.2017.07.012","article-title":"Serum exosomal protein profiling for the non-invasive detection of cardiac allograft rejection","volume":"37","author":"Kennel","year":"2018","journal-title":"J. Heart Lung Transplant."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.3390\/molecules19021568","article-title":"miRNA in plasma exosome is stable under different storage conditions","volume":"19","author":"Ge","year":"2014","journal-title":"Molecules"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.3892\/mmr.2015.3919","article-title":"Assessment of endogenous reference gene suitability for serum exosomal microRNA expression analysis in liver carcinoma resection studies","volume":"12","author":"Li","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"E1681","DOI":"10.1210\/jc.2013-3843","article-title":"Plasma exosome microRNA profiling unravels a new potential modulator of adiponectin pathway in diabetes: Effect of glycemic control","volume":"99","author":"Santovito","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lange, T., Stracke, S., Rettig, R., Lendeckel, U., Kuhn, J., Schl\u00fcter, R., Rippe, V., Endlich, K., and Endlich, N. (2017). Identification of miR-16 as an endogenous reference gene for the normalization of urinary exosomal miRNA expression data from CKD patients. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183435"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1097\/JTO.0b013e318299ac32","article-title":"microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer","volume":"8","author":"Cazzoli","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ragni, E., Perucca Orfei, C., De Luca, P., Colombini, A., Vigan\u00f2, M., Lugano, G., Bollati, V., and de Girolamo, L. (2019). Identification of miRNA Reference Genes in Extracellular Vesicles from Adipose Derived Mesenchymal Stem Cells for Studying Osteoarthritis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051108"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"121630","DOI":"10.1172\/jci.insight.121630","article-title":"The complex landscape of microRNAs in articular cartilage: Biology, pathology, and therapeutic targets","volume":"3","author":"Endisha","year":"2018","journal-title":"JCI Insight"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cavalleri, T., Angelici, L., Favero, C., Dioni, L., Mensi, C., Bareggi, C., Palleschi, A., Rimessi, A., Consonni, D., and Bordini, L. (2017). Author information Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176680"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Vandesompele, J., de Preter, K., Pattyn, F., Poppe, B., van Roy, N., De Paepe, A., and Speleman, F. (2002). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol., 3.","DOI":"10.1186\/gb-2002-3-7-research0034"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5245","DOI":"10.1158\/0008-5472.CAN-04-0496","article-title":"Normalization of real-time quantitative reverse transcription-PCR data: A model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets","volume":"64","author":"Andersen","year":"2004","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1023\/B:BILE.0000019559.84305.47","article-title":"Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper--Excel-based tool using pair-wise correlations","volume":"26","author":"Pfaffl","year":"2004","journal-title":"Biotechnol. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Silver, N., Best, S., Jiang, J., and Thein, S.L. (2006). Selection of housekeeping genes for gene expression studies in human reticulocytes using real-time PCR. BMC Mol. Biol., 7.","DOI":"10.1186\/1471-2199-7-33"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"W566","DOI":"10.1093\/nar\/gkv468","article-title":"ClustVis: A web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap","volume":"43","author":"Metsalu","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D90","DOI":"10.1093\/nar\/gkw926","article-title":"miRPathDB: A new dictionary on microRNAs and target pathways","volume":"45","author":"Backes","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Nishimura, D. (2001). BioCarta. Biotech Soft. Int. Rep.","DOI":"10.1089\/152791601750294344"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Mieczkowska, A., Schumacher, A., Filipowicz, N., Wardowska, A., Zieli\u0144ski, M., Madanecki, P., Nowicka, E., Langa, P., Deptu\u0142a, M., and Zieli\u0144ski, J. (2018). Immunophenotyping and transcriptional profiling of in vitro cultured human adipose tissue derived stem cells. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-29477-5"},{"key":"ref_43","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_44","doi-asserted-by":"crossref","unstructured":"Mestdagh, P., van Vlierberghe, P., de Weer, A., Muth, D., Westermann, F., Speleman, F., and Vandesompele, J. (2009). A novel and universal method for microRNA RT-qPCR data normalization. Genome Biol., 10.","DOI":"10.1186\/gb-2009-10-6-r64"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1042\/BST20180079","article-title":"MSC exosome works through a protein-based mechanism of action","volume":"46","author":"Toh","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wang, X., Takagawa, J., Lam, V.C., Haddad, D.J., Tobler, D.L., Mok, P.Y., Zhang, Y., Clifford, B.T., Pinnamaneni, K., and Saini, S.A. (2011). Donor myocardial infarction impairs the therapeutic potential of bone marrow cells by an interleukin-1-mediated inflammatory response. Sci. Transl. Med., 3.","DOI":"10.1126\/scitranslmed.3002814"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1038\/mt.2014.191","article-title":"MSCs isolated from patients with ischemic vascular disease have normal angiogenic potential","volume":"22","year":"2014","journal-title":"Mol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1093\/rheumatology\/kel267","article-title":"Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors and auto-immune disease patients reduce the proliferation of autologous- and allogeneic-stimulated lymphocytes in vitro","volume":"46","author":"Bracci","year":"2007","journal-title":"Rheumatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.exphem.2005.05.006","article-title":"T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia","volume":"33","author":"Bacigalupo","year":"2005","journal-title":"Exp. Hematol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1002\/art.10118","article-title":"Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis","volume":"46","author":"Murphy","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1002\/art.22035","article-title":"Bone marrow endothelial progenitors are defective in systemic sclerosis","volume":"54","author":"Quirici","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1136\/ard.2007.076174","article-title":"Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis","volume":"67","author":"Kastrinaki","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/sj.bmt.1705179","article-title":"Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis","volume":"36","author":"Papadaki","year":"2005","journal-title":"Bone Marrow Transplant."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1177\/1352458510371959","article-title":"Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis","volume":"16","author":"Mallam","year":"2010","journal-title":"Mult. Scler."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jneuroim.2008.05.006","article-title":"Differences in mesenchymal stem cell cytokine profiles between MS patients and healthy donors: Implication for assessment of disease activity and treatment","volume":"199","author":"Mazzanti","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1186\/s12967-014-0243-9","article-title":"Advancing stem cell therapy from bench to bedside: Lessons from drug therapies","volume":"12","author":"Srijaya","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.stem.2015.06.007","article-title":"Stem cell therapies in clinical trials: Progress and challenges","volume":"17","author":"Trounson","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_58","first-page":"1","article-title":"Is it possible to improve the success rate of cellular therapies based on mesenchymal stem cells?","volume":"1","author":"Galderisi","year":"2014","journal-title":"J. Stem Cells Res. Rev. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cyto.2010.01.004","article-title":"Secretion profile of human bone marrow stromal cells: Donor variability and response to inflammatory stimuli","volume":"50","author":"Zhukareva","year":"2010","journal-title":"Cytokine"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1142\/S2339547816500084","article-title":"Donor variability among anti-inflammatory pre-activated mesenchymal stromal cells","volume":"4","author":"Gray","year":"2016","journal-title":"Technology"},{"key":"ref_61","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_62","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1038\/s41598-018-19581-x","article-title":"The microRNA regulatory landscape of MSC-derived exosomes: A systems view","volume":"8","author":"Ferguson","year":"2018","journal-title":"Sci Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6305295","DOI":"10.1155\/2017\/6305295","article-title":"Focus on Mesenchymal Stem Cell-Derived Exosomes: Opportunities and Challenges in Cell-Free Therapy","volume":"2017","author":"Cheng","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.semcdb.2016.11.008","article-title":"MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment","volume":"67","author":"Toh","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1373\/clinchem.2015.239459","article-title":"Data Normalization Strategies for MicroRNA Quantification","volume":"61","author":"Schwarzenbach","year":"2015","journal-title":"Clin. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1007\/s10529-010-0380-z","article-title":"Normalization strategies for microRNA profiling experiments: A \u2018normal\u2019 way to a hidden layer of complexity?","volume":"32","author":"Meyer","year":"2010","journal-title":"Biotechnol. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1161\/CIRCRESAHA.116.304360","article-title":"Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology","volume":"116","author":"Gray","year":"2015","journal-title":"Circ. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.devcel.2016.12.001","article-title":"Exosomal MicroRNA Transport from Salivary Mesenchyme Regulates Epithelial Progenitor Expansion during Organogenesis","volume":"40","author":"Hayashi","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature01957","article-title":"The nuclear RNase III Drosha initiates microRNA processing","volume":"425","author":"Lee","year":"2003","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1302\/2046-3758.510.BJR-2016-0074.R2","article-title":"Silencing of microRNA-138-5p promotes IL-1\u03b2-induced cartilage degradation in human chondrocytes by targeting FOXC1: miR-138 promotes cartilage degradation","volume":"5","author":"Yuan","year":"2016","journal-title":"Bone Joint Res."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Yoshida, M., Hata, K., Takashima, R., Ono, K., Nakamura, E., Takahata, Y., Murakami, T., Iseki, S., Takano-Yamamoto, T., and Nishimura, R. (2015). The transcription factor Foxc1 is necessary for Ihh-Gli2-regulated endochondral ossification. Nat. Commun., 6.","DOI":"10.1038\/ncomms7653"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Nakamura, A., Rampersaud, Y.R., Sharma, A., Lewis, S.J., Wu, B., Datta, P., Sundararajan, K., Endisha, H., Rossomacha, E., and Rockel, J.S. (2016). Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degeneration. JCI Insight, 1.","DOI":"10.1172\/jci.insight.86820"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.ymthe.2016.12.020","article-title":"Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2","volume":"25","author":"Wang","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"R58","DOI":"10.1186\/ar4494","article-title":"p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis","volume":"16","author":"Philipot","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.3892\/or.2017.5475","article-title":"Upregulation of microRNA-125b-5p is involved in the pathogenesis of osteoarthritis by downregulating SYVN1","volume":"37","author":"Ge","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbacli.2014.11.009","article-title":"MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis","volume":"3","author":"Song","year":"2014","journal-title":"BBA Clin."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Jia, J., Yang, S., Liu, X., Ye, S., and Tian, H. (2014). MicroRNA-21 controls the development of osteoarthritis by targeting GDF-5 in chondrocytes. Exp. Mol. Med., 46.","DOI":"10.1038\/emm.2013.152"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4775","DOI":"10.1002\/jcb.26669","article-title":"MicroRNA-193b-3p regulates matrix metalloproteinase 19 expression in interleukin-1\u03b2-induced human chondrocytes","volume":"119","author":"Chang","year":"2018","journal-title":"J. Cell Biochem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/4\/369\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:46:35Z","timestamp":1760186795000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/4\/369"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,23]]},"references-count":79,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["cells8040369"],"URL":"https:\/\/doi.org\/10.3390\/cells8040369","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,23]]}}}