{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:05:03Z","timestamp":1792677903336,"version":"4.5.0"},"reference-count":93,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2017,6,3]],"date-time":"2017-06-03T00:00:00Z","timestamp":1496448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Extracellular vesicles (EVs) derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research and to develop safe and efficacious therapies, whilst taking into account the applicable regulations. Here, we discuss the requirements for manufacturing, safety, and efficacy testing of EVs along their path from the laboratory to the patient. Development of EV-therapeutics is influenced by the source cell types and the target diseases. In this article, we express our view based on our experience in manufacturing biological therapeutics for routine use or clinical testing, and focus on strategies for advancing mesenchymal stromal cell (MSC)-derived EV-based therapies. We also discuss the rationale for testing MSC-EVs in selected diseases with an unmet clinical need such as critical size bone defects, epidermolysis bullosa and spinal cord injury. While the scientific community, pharmaceutical companies and clinicians are at the point of entering into clinical trials for testing the therapeutic potential of various EV-based products, the identification of the mode of action underlying the suggested potency in each therapeutic approach remains a major challenge to the translational path.<\/jats:p>","DOI":"10.3390\/ijms18061190","type":"journal-article","created":{"date-parts":[[2017,6,6]],"date-time":"2017-06-06T10:53:09Z","timestamp":1496746389000},"page":"1190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":307,"title":["Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use"],"prefix":"10.3390","volume":"18","author":[{"given":"Mario","family":"Gimona","sequence":"first","affiliation":[{"name":"GMP Unit, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria"},{"name":"Research Program Nanovesicular Therapies, Paracelsus Medical University (PMU), 5020 Salzburg, Austria"},{"name":"Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University (PMU), 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Pachler","sequence":"additional","affiliation":[{"name":"GMP Unit, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria"},{"name":"Research Program Nanovesicular Therapies, Paracelsus Medical University (PMU), 5020 Salzburg, Austria"},{"name":"Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University (PMU), 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1416-6023","authenticated-orcid":false,"given":"Sandra","family":"Laner-Plamberger","sequence":"additional","affiliation":[{"name":"GMP Unit, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria"},{"name":"Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University (PMU), 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Schallmoser","sequence":"additional","affiliation":[{"name":"GMP Unit, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria"},{"name":"Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University (PMU), 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Rohde","sequence":"additional","affiliation":[{"name":"GMP Unit, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria"},{"name":"Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University (PMU), 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1007\/s00018-011-0689-3","article-title":"Membrane vesicles, current state-of-the-art: Emerging role of extracellular vesicles","volume":"68","author":"Gyorgy","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/nm0598-594","article-title":"Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes","volume":"4","author":"Zitvogel","year":"1998","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0022-1759(02)00330-7","article-title":"Production and characterization of clinical grade exosomes derived from dendritic cells","volume":"270","author":"Lamparski","year":"2002","journal-title":"J. Immunol. Methods"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1479-5876-3-10","article-title":"Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: Results of thefirst phase I clinical trial","volume":"3","author":"Escudier","year":"2005","journal-title":"J. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1479-5876-3-9","article-title":"A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer","volume":"3","author":"Morse","year":"2005","journal-title":"J. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1071008","DOI":"10.1080\/2162402X.2015.1071008","article-title":"Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC","volume":"5","author":"Besse","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"30087","DOI":"10.3402\/jev.v4.30087","article-title":"Applying extracellular vesicles based therapeutics in clinical trials-An ISEV position paper","volume":"4","author":"Lener","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev-pharmtox-061616-030146","article-title":"Stem Cell Extracellular Vesicles: Extended Messages of Regeneration","volume":"57","author":"Riazifar","year":"2017","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.scr.2009.12.003","article-title":"Exosome secreted by MSC reduces myocardial ischemia\/reperfusion injury","volume":"4","author":"Lai","year":"2010","journal-title":"Stem Cell Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1479-5876-9-47","article-title":"Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs","volume":"9","author":"Chen","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tan, S.S., Yin, Y., Lee, T., Lai, R.C., Yeo, R.W., Zhang, B., Choo, A., and Lim, S.K. (2013). Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane. J. Extracell. Vesicles.","DOI":"10.3402\/jev.v2i0.22614"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/nrd3978","article-title":"Extracellular vesicles: Biology and emerging therapeutic opportunities","volume":"12","author":"Mager","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1089\/scd.2013.0479","article-title":"Mesenchymal stem cells secrete immunologically active exosomes","volume":"23","author":"Zhang","year":"2014","journal-title":"Stem Cells Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/s12015-014-9545-9","article-title":"A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles","volume":"11","author":"Akyurekli","year":"2015","journal-title":"Stem Cell Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1089\/ten.teb.2014.0300","article-title":"Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine","volume":"21","author":"Lamichhane","year":"2015","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1089\/hum.2015.072","article-title":"Therapeutic Potential of Multipotent Mesenchymal Stromal Cells and Their Extracellular Vesicles","volume":"26","author":"Heldring","year":"2015","journal-title":"Hum. Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/mt.2015.44","article-title":"Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-Free Therapeutic Applications","volume":"23","author":"Rani","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1929536","DOI":"10.1155\/2016\/1929536","article-title":"Exosomes from Human Umbilical Cord Mesenchymal Stem Cells: Identification, Purification, and Biological Characteristics","volume":"2016","author":"Zhang","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3886","DOI":"10.1021\/acsnano.5b08015","article-title":"Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine","volume":"10","author":"Fais","year":"2016","journal-title":"ACS Nano"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1007\/s10495-016-1292-8","article-title":"Peripheral blood mononuclear cell secretome for tissue repair","volume":"21","author":"Beer","year":"2016","journal-title":"Apoptosis"},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/gt.2017.8","article-title":"Extracellular vesicles for nucleic acid delivery: Progress and prospects for safe RNA-based gene therapy","volume":"24","author":"Jiang","year":"2017","journal-title":"Gene Ther."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nbt.2971","article-title":"An FDA perspective on preclinical development of cell-based regenerative medicine products","volume":"32","author":"Bailey","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/6529","article-title":"Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta","volume":"5","author":"Horwitz","year":"1999","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.bone.2004.06.013","article-title":"Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis\u2014A preliminary result of three cases","volume":"35","author":"Kitoh","year":"2004","journal-title":"Bone"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3727\/000000004783983909","article-title":"Translational research for injectable tissue-engineered bone regeneration using mesenchymal stem cells and platelet-rich plasma: From basic research to clinical case study","volume":"13","author":"Yamada","year":"2004","journal-title":"Cell Transplant."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1089\/1076327041348284","article-title":"Autogenous injectable bone for regeneration with mesenchymal stem cells and platelet-rich plasma: Tissue-engineered bone regeneration","volume":"10","author":"Yamada","year":"2004","journal-title":"Tissue Eng."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/jbm.a.30248","article-title":"Osteogenic potential of injectable tissue-engineered bone: A comparison among autogenous bone, bone substitute (Bio-oss), platelet-rich plasma, and tissue-engineered bone with respect to their mechanical properties and histological findings","volume":"73","author":"Ito","year":"2005","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1186\/s13287-015-0256-1","article-title":"Combining mesenchymal stem cell sheets with platelet-rich plasma gel\/calcium phosphate particles: A novel strategy to promote bone regeneration","volume":"6","author":"Qi","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/jbmr.185","article-title":"Fracture healing is accelerated in the absence of the adaptive immune system","volume":"26","author":"Toben","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1089\/ten.teb.2011.0182","article-title":"Harnessing and modulating inflammation in strategies for bone regeneration","volume":"17","author":"Mountziaris","year":"2011","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40634-014-0017-6","article-title":"Immune modulation as a therapeutic strategy in bone regeneration","volume":"2","author":"Schlundt","year":"2015","journal-title":"J. Exp. Orthop."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3389\/fimmu.2014.00556","article-title":"Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells Derived Exosomes on in vitro Stimulated T Cells","volume":"5","author":"Blazquez","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1007\/s12026-016-8798-6","article-title":"Immunomodulatory effects of mesenchymal stromal cells-derived exosome","volume":"64","author":"Chen","year":"2016","journal-title":"Immunol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"24120","DOI":"10.1038\/srep24120","article-title":"Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions","volume":"6","author":"Bassi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/1873-3468.12024","article-title":"Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression","volume":"590","author":"Cui","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21961","DOI":"10.1038\/srep21961","article-title":"Bone marrow stromal\/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo","volume":"6","author":"Qin","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1016\/j.joca.2016.06.022","article-title":"Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration","volume":"24","author":"Zhang","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"232","DOI":"10.7150\/ijbs.16951","article-title":"Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis","volume":"13","author":"Liu","year":"2017","journal-title":"Int. J. Biol. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45622","DOI":"10.1038\/srep45622","article-title":"Extracellular Vesicle-functionalized Decalcified Bone Matrix Scaffolds with Enhanced Pro-angiogenic and Pro-bone Regeneration Activities","volume":"7","author":"Xie","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.jaad.2014.01.903","article-title":"Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification","volume":"70","author":"Fine","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.jaad.2009.03.053","article-title":"Extracutaneous manifestations and complications of inherited epidermolysis bullosa: Part II. Other organs","volume":"61","author":"Fine","year":"2009","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1038\/jid.2015.158","article-title":"Potential of Systemic Allogeneic Mesenchymal Stromal Cell Therapy for Children with Recessive Dystrophic Epidermolysis Bullosa","volume":"135","author":"Petrof","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1002\/stem.1771","article-title":"HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing","volume":"33","author":"Zhang","year":"2015","journal-title":"Stem Cells"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1002\/stem.2432","article-title":"HucMSC Exosome-Delivered 14-3-3\u03b6 Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration","volume":"34","author":"Zhang","year":"2016","journal-title":"Stem Cells"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"32993","DOI":"10.1038\/srep32993","article-title":"Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts","volume":"6","author":"Hu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5683","DOI":"10.1038\/ncomms6683","article-title":"A recoverable state of axon injury persists for hours after spinal cord contusion in vivo","volume":"5","author":"Williams","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1111\/j.1460-9568.2011.07643.x","article-title":"MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish","volume":"33","author":"Yu","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/stem.1129","article-title":"Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth","volume":"30","author":"Xin","year":"2012","journal-title":"Stem Cells"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1002\/stem.1409","article-title":"miR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles","volume":"31","author":"Xin","year":"2013","journal-title":"Stem Cells"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s13287-015-0202-2","article-title":"Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury","volume":"6","author":"Neirinckx","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.5966\/sctm.2015-0078","article-title":"Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression","volume":"4","author":"Doeppner","year":"2015","journal-title":"Stem Cells Transl. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/jnc.13036","article-title":"Exosome-mediated inflammasome signaling after central nervous system injury","volume":"136","author":"Brand","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1007\/s12013-014-0354-1","article-title":"Anti-inflammatory Mechanism of Bone Marrow Mesenchymal Stem Cell Transplantation in Rat Model of Spinal Cord Injury","volume":"71","author":"Han","year":"2015","journal-title":"Cell Biochem. Biophys."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1007\/s12015-014-9576-2","article-title":"Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural\/glial proliferation and differentiation","volume":"11","author":"Teixeira","year":"2015","journal-title":"Stem Cell Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"634","DOI":"10.5966\/sctm.2016-0071","article-title":"Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal Behavior in a Rat Model of Parkinson\u2019s Disease","volume":"6","author":"Teixeira","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nrrheum.2014.19","article-title":"Emerging role of extracellular vesicles in inflammatory diseases","volume":"10","author":"Buzas","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1128\/MMBR.64.3.515-547.2000","article-title":"Signal peptide-dependent protein transport in Bacillus subtilis: A genome-based survey of the secretome","volume":"64","author":"Tjalsma","year":"2000","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.expneurol.2015.03.013","article-title":"The secretome of apoptotic human peripheral blood mononuclear cells attenuates secondary damage following spinal cord injury in rats","volume":"267","author":"Haider","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1172\/JCI101508","article-title":"Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. I. The Characterization of the Protein Fractions of Human Plasma","volume":"23","author":"Cohn","year":"1944","journal-title":"J. Clin. Investig."},{"key":"ref_62","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_63","doi-asserted-by":"crossref","first-page":"29828","DOI":"10.3402\/jev.v5.29828","article-title":"MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA","volume":"5","author":"Lai","year":"2016","journal-title":"J. Extracell. Vesicles"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"22519","DOI":"10.1038\/srep22519","article-title":"Cells release subpopulations of exosomes with distinct molecular and biological properties","volume":"6","author":"Willms","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1074\/mcp.M112.021303","article-title":"Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids","volume":"12","author":"Tauro","year":"2013","journal-title":"Mol. Cell. Proteomics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1172\/JCI81129","article-title":"Extracellular vesicle isolation and characterization: Toward clinical application","volume":"126","author":"Xu","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"10266","DOI":"10.1038\/srep10266","article-title":"Heparin affinity purification of extracellular vesicles","volume":"5","author":"Balaj","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_68","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_69","doi-asserted-by":"crossref","first-page":"E3536","DOI":"10.1073\/pnas.1703920114","article-title":"Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus","volume":"114","author":"Long","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"32945","DOI":"10.3402\/jev.v5.32945","article-title":"Techniques used for the isolation and characterization of extracellular vesicles: Results of a worldwide survey","volume":"5","author":"Gardiner","year":"2016","journal-title":"J. Extracell. Vesicles"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.chroma.2014.10.026","article-title":"Benchtop isolation and characterization of functional exosomes by sequential filtration","volume":"1371","author":"Heinemann","year":"2014","journal-title":"J. Chromatogr. A"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"33641","DOI":"10.1038\/srep33641","article-title":"Size-Exclusion Chromatography-based isolation minimally alters Extracellular Vesicles\u2019 characteristics compared to precipitating agents","volume":"6","author":"Franquesa","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_73","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_74","doi-asserted-by":"crossref","first-page":"29","DOI":"10.23937\/2469-570X\/1410029","article-title":"Mesenchymal Stem Cell: Considerations for Manufacturing and Clinical Trials on Cell Therapy Product","volume":"3","author":"Chen","year":"2016","journal-title":"Int. J. Stem Cell Res. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13287-016-0370-8","article-title":"Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production","volume":"7","author":"Camilleri","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"16766","DOI":"10.1073\/pnas.1416121111","article-title":"TSG-6 as a biomarker to predict efficacy of human mesenchymal stem\/progenitor cells (hMSCs) in modulating sterile inflammation in vivo","volume":"111","author":"Lee","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1002\/stem.1982","article-title":"Establishing criteria for human mesenchymal stem cell potency","volume":"33","author":"Samsonraj","year":"2015","journal-title":"Stem Cells"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"26913","DOI":"10.3402\/jev.v3.26913","article-title":"Minimal experimental requirements for definition of extracellular vesicles and their functions: A position statement from the International Society for Extracellular Vesicles","volume":"3","author":"Lotvall","year":"2014","journal-title":"J. Extracell. Vesicles"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"O\u2019Loughlin, A.J., Mager, I., de Jong, O.G., Varela, M.A., Schiffelers, R.M., El Andaloussi, S., Wood, M.J., and Vader, P. (2017). Functional Delivery of Lipid-Conjugated siRNA by Extracellular Vesicles. Mol. Ther.","DOI":"10.1016\/j.ymthe.2017.03.021"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.nano.2015.10.012","article-title":"Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells","volume":"12","author":"Kim","year":"2016","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"297","DOI":"10.4252\/wjsc.v8.i9.297","article-title":"Stem cell-derived exosomes as a therapeutic tool for cardiovascular disease","volume":"8","author":"Suzuki","year":"2016","journal-title":"World J. Stem Cells"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/mt.2008.1","article-title":"Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer","volume":"16","author":"Dai","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Di Rocco, G., Baldari, S., and Toietta, G. (2016). Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis. Stem Cells Int.","DOI":"10.1155\/2016\/5029619"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.1158\/0008-5472.CAN-16-0868","article-title":"The Biodistribution and Immune Suppressive Effects of Breast Cancer-Derived Exosomes","volume":"76","author":"Wen","year":"2016","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Morishita, M., Takahashi, Y., Nishikawa, M., and Takakura, Y. (2017). Pharmacokinetics of Exosomes-An Important Factor for Elucidating the Biological Roles of Exosomes and for the Development of Exosome-Based Therapeutics. J. Pharm. Sci.","DOI":"10.1016\/j.xphs.2017.02.030"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7029","DOI":"10.1038\/ncomms8029","article-title":"Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters","volume":"6","author":"Lai","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jbiotec.2013.03.013","article-title":"Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection","volume":"165","author":"Takahashi","year":"2013","journal-title":"J. Biotechnol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Mateescu, B., Kowal, E.J., van Balkom, B.W., Bartel, S., Bhattacharyya, S.N., Buzas, E.I., Buck, A.H., de Candia, P., Chow, F.W., and Das, S. (2017). Obstacles and opportunities in the functional analysis of extracellular vesicle RNA\u2014An ISEV position paper. J. Extracell. Vesicles.","DOI":"10.1080\/20013078.2017.1286095"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.stem.2009.05.003","article-title":"Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6","volume":"5","author":"Lee","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/leu.2014.41","article-title":"MSC-derived exosomes: A novel tool to treat therapy-refractory graft-versus-host disease","volume":"28","author":"Kordelas","year":"2014","journal-title":"Leukemia"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s12967-016-0838-4","article-title":"Changing R&D models in research-based pharmaceutical companies","volume":"14","author":"Schuhmacher","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s13287-015-0145-7","article-title":"Translating stem cell research to the clinic: A primer on translational considerations for your first stem cell protocol","volume":"6","author":"Creane","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1056\/NEJMra1612575","article-title":"Academic, Foundation, and Industry Collaboration in Finding New Therapies","volume":"376","author":"Ramsey","year":"2017","journal-title":"N. Engl. J. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/6\/1190\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:37:56Z","timestamp":1760207876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/6\/1190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,3]]},"references-count":93,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2017,6]]}},"alternative-id":["ijms18061190"],"URL":"https:\/\/doi.org\/10.3390\/ijms18061190","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,3]]}}}