Independent human mesenchymal stromal cell–derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine graft-versus-host disease model
Extracellular vesicles (EVs) harvested from conditioned media of human mesenchymal stromal cells (MSCs) suppress acute inflammation in various disease models and promote regeneration of damaged tissues. After successful treatment of a patient with acute steroid-refractory graft-versus-host disease (...
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Veröffentlicht in: | Cytotherapy (Oxford, England) England), 2023-08, Vol.25 (8), p.821-836 |
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creator | Madel, Rabea J. Börger, Verena Dittrich, Robin Bremer, Michel Tertel, Tobias Phuong, Nhi Ngo Thi Baba, Hideo A. Kordelas, Lambros Staubach, Simon Stein, Frank Haberkant, Per Hackl, Matthias Grillari, Regina Grillari, Johannes Buer, Jan Horn, Peter A. Westendorf, Astrid M. Brandau, Sven Kirschning, Carsten J. Giebel, Bernd |
description | Extracellular vesicles (EVs) harvested from conditioned media of human mesenchymal stromal cells (MSCs) suppress acute inflammation in various disease models and promote regeneration of damaged tissues. After successful treatment of a patient with acute steroid-refractory graft-versus-host disease (GVHD) using EVs prepared from conditioned media of human bone marrow–derived MSCs, this study focused on improving the MSC-EV production for clinical application.
Independent MSC-EV preparations all produced according to a standardized procedure revealed broad immunomodulatory differences. Only a proportion of the MSC-EV products applied effectively modulated immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences in vivo, at first a mouse GVHD model was optimized.
The functional testing of selected MSC-EV preparations demonstrated that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GVHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also failed to modulate GVHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, no concrete proteins or miRNAs were identified that could serve as surrogate markers.
Standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency before administration to patients. Here, upon comparing immunomodulating capabilities of independent MSC-EV preparations in vivo and in vitro, we found that the mdMLR assay was qualified for such analyses. |
doi_str_mv | 10.1016/j.jcyt.2023.03.008 |
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Independent MSC-EV preparations all produced according to a standardized procedure revealed broad immunomodulatory differences. Only a proportion of the MSC-EV products applied effectively modulated immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences in vivo, at first a mouse GVHD model was optimized.
The functional testing of selected MSC-EV preparations demonstrated that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GVHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also failed to modulate GVHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, no concrete proteins or miRNAs were identified that could serve as surrogate markers.
Standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency before administration to patients. Here, upon comparing immunomodulating capabilities of independent MSC-EV preparations in vivo and in vitro, we found that the mdMLR assay was qualified for such analyses.</description><identifier>ISSN: 1465-3249</identifier><identifier>EISSN: 1477-2566</identifier><identifier>DOI: 10.1016/j.jcyt.2023.03.008</identifier><identifier>PMID: 37055321</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Animals ; Culture Media, Conditioned - metabolism ; exosomes ; extracellular vesicles ; Extracellular Vesicles - metabolism ; Graft vs Host Disease - therapy ; graft-versus-host disease ; heterogeneity ; Humans ; mesenchymal stem cells ; Mesenchymal Stem Cells - metabolism ; mesenchymal stromal cells ; Mice ; MicroRNAs - genetics ; MicroRNAs - metabolism</subject><ispartof>Cytotherapy (Oxford, England), 2023-08, Vol.25 (8), p.821-836</ispartof><rights>2023 International Society for Cell & Gene Therapy</rights><rights>Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-20a73f84a96bc0567161fd4698fc09411ac945a095e5c8eb1c2be869e00c57133</citedby><cites>FETCH-LOGICAL-c400t-20a73f84a96bc0567161fd4698fc09411ac945a095e5c8eb1c2be869e00c57133</cites><orcidid>0000-0002-2702-4163 ; 0000-0002-8230-2218 ; 0000-0003-2446-948X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37055321$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Madel, Rabea J.</creatorcontrib><creatorcontrib>Börger, Verena</creatorcontrib><creatorcontrib>Dittrich, Robin</creatorcontrib><creatorcontrib>Bremer, Michel</creatorcontrib><creatorcontrib>Tertel, Tobias</creatorcontrib><creatorcontrib>Phuong, Nhi Ngo Thi</creatorcontrib><creatorcontrib>Baba, Hideo A.</creatorcontrib><creatorcontrib>Kordelas, Lambros</creatorcontrib><creatorcontrib>Staubach, Simon</creatorcontrib><creatorcontrib>Stein, Frank</creatorcontrib><creatorcontrib>Haberkant, Per</creatorcontrib><creatorcontrib>Hackl, Matthias</creatorcontrib><creatorcontrib>Grillari, Regina</creatorcontrib><creatorcontrib>Grillari, Johannes</creatorcontrib><creatorcontrib>Buer, Jan</creatorcontrib><creatorcontrib>Horn, Peter A.</creatorcontrib><creatorcontrib>Westendorf, Astrid M.</creatorcontrib><creatorcontrib>Brandau, Sven</creatorcontrib><creatorcontrib>Kirschning, Carsten J.</creatorcontrib><creatorcontrib>Giebel, Bernd</creatorcontrib><title>Independent human mesenchymal stromal cell–derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine graft-versus-host disease model</title><title>Cytotherapy (Oxford, England)</title><addtitle>Cytotherapy</addtitle><description>Extracellular vesicles (EVs) harvested from conditioned media of human mesenchymal stromal cells (MSCs) suppress acute inflammation in various disease models and promote regeneration of damaged tissues. After successful treatment of a patient with acute steroid-refractory graft-versus-host disease (GVHD) using EVs prepared from conditioned media of human bone marrow–derived MSCs, this study focused on improving the MSC-EV production for clinical application.
Independent MSC-EV preparations all produced according to a standardized procedure revealed broad immunomodulatory differences. Only a proportion of the MSC-EV products applied effectively modulated immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences in vivo, at first a mouse GVHD model was optimized.
The functional testing of selected MSC-EV preparations demonstrated that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GVHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also failed to modulate GVHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, no concrete proteins or miRNAs were identified that could serve as surrogate markers.
Standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency before administration to patients. Here, upon comparing immunomodulating capabilities of independent MSC-EV preparations in vivo and in vitro, we found that the mdMLR assay was qualified for such analyses.</description><subject>Animals</subject><subject>Culture Media, Conditioned - metabolism</subject><subject>exosomes</subject><subject>extracellular vesicles</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Graft vs Host Disease - therapy</subject><subject>graft-versus-host disease</subject><subject>heterogeneity</subject><subject>Humans</subject><subject>mesenchymal stem cells</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>mesenchymal stromal cells</subject><subject>Mice</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><issn>1465-3249</issn><issn>1477-2566</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-KFDEQxoMo7jr6Ah4kRy89VtL_0uBFllUXFrzoOWTS1U6GTrpNpQf75jv4IL6TT2KaWT0KRVUovvoVlY-xlwL2AkTz5rQ_2TXtJchyDzlAPWLXomrbQtZN83h7N3VRyqq7Ys-ITgASlKqfsquyhboupbhmv-5CjzPmFBI_Lt4E7pEw2OPqzcgpxWmrFsfx94-fPUZ3xp7j9xTN1ltGE_kZydkR-RxxNtEkNwXivRsGjJnqzDiu3KSEYTEJOa1-TpMn7gLP20x_NsFmpl-iC8i_RjOk4oyRFiqOE6VMIjSE3E89js_Zk8GMhC8e6o59eX_7-eZjcf_pw93Nu_vCVgCpkGDaclCV6ZqDhbppRSOGvmo6NVjoKiGM7araQFdjbRUehJUHVE2HALZuRVnu2OsLd47TtwUpae9ou9gEnBbSUoHolISs3TF5kdo4EUUc9BydN3HVAvRmlD7pzSi9GaUhB6g89OqBvxw89v9G_jqTBW8vAsxXnh1GTdbh9lMuok26n9z_-H8A_HyrLA</recordid><startdate>202308</startdate><enddate>202308</enddate><creator>Madel, Rabea J.</creator><creator>Börger, Verena</creator><creator>Dittrich, Robin</creator><creator>Bremer, Michel</creator><creator>Tertel, Tobias</creator><creator>Phuong, Nhi Ngo Thi</creator><creator>Baba, Hideo A.</creator><creator>Kordelas, Lambros</creator><creator>Staubach, Simon</creator><creator>Stein, Frank</creator><creator>Haberkant, Per</creator><creator>Hackl, Matthias</creator><creator>Grillari, Regina</creator><creator>Grillari, Johannes</creator><creator>Buer, Jan</creator><creator>Horn, Peter A.</creator><creator>Westendorf, Astrid M.</creator><creator>Brandau, Sven</creator><creator>Kirschning, Carsten J.</creator><creator>Giebel, Bernd</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2702-4163</orcidid><orcidid>https://orcid.org/0000-0002-8230-2218</orcidid><orcidid>https://orcid.org/0000-0003-2446-948X</orcidid></search><sort><creationdate>202308</creationdate><title>Independent human mesenchymal stromal cell–derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine graft-versus-host disease model</title><author>Madel, Rabea J. ; 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After successful treatment of a patient with acute steroid-refractory graft-versus-host disease (GVHD) using EVs prepared from conditioned media of human bone marrow–derived MSCs, this study focused on improving the MSC-EV production for clinical application.
Independent MSC-EV preparations all produced according to a standardized procedure revealed broad immunomodulatory differences. Only a proportion of the MSC-EV products applied effectively modulated immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences in vivo, at first a mouse GVHD model was optimized.
The functional testing of selected MSC-EV preparations demonstrated that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GVHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also failed to modulate GVHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, no concrete proteins or miRNAs were identified that could serve as surrogate markers.
Standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency before administration to patients. Here, upon comparing immunomodulating capabilities of independent MSC-EV preparations in vivo and in vitro, we found that the mdMLR assay was qualified for such analyses.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>37055321</pmid><doi>10.1016/j.jcyt.2023.03.008</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-2702-4163</orcidid><orcidid>https://orcid.org/0000-0002-8230-2218</orcidid><orcidid>https://orcid.org/0000-0003-2446-948X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Culture Media, Conditioned - metabolism exosomes extracellular vesicles Extracellular Vesicles - metabolism Graft vs Host Disease - therapy graft-versus-host disease heterogeneity Humans mesenchymal stem cells Mesenchymal Stem Cells - metabolism mesenchymal stromal cells Mice MicroRNAs - genetics MicroRNAs - metabolism |
title | Independent human mesenchymal stromal cell–derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine graft-versus-host disease model |
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