Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity
IntroductionMSCs exhibit regenerative, anti-inflammatory and immunomodulatory properties due to the large amount of cytokines, chemokines and growth factors they secrete. MSCs have been extensively evaluated in clinical trials, however, in some cases their therapeutic effects are variable. Therefore...
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2025-02-01
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| author | Jaris Valencia Jaris Valencia Jaris Valencia Rosa M. Yáñez Rosa M. Yáñez Rosa M. Yáñez Sandra Muntión Sandra Muntión Sandra Muntión María Fernández-García María Fernández-García María Fernández-García Jorge Diego Martín-Rufino Jorge Diego Martín-Rufino Agustín G. Zapata Agustín G. Zapata Agustín G. Zapata Juan A. Bueren Juan A. Bueren Juan A. Bueren Ángeles Vicente Ángeles Vicente Ángeles Vicente Fermín Sánchez-Guijo Fermín Sánchez-Guijo Fermín Sánchez-Guijo |
| author_facet | Jaris Valencia Jaris Valencia Jaris Valencia Rosa M. Yáñez Rosa M. Yáñez Rosa M. Yáñez Sandra Muntión Sandra Muntión Sandra Muntión María Fernández-García María Fernández-García María Fernández-García Jorge Diego Martín-Rufino Jorge Diego Martín-Rufino Agustín G. Zapata Agustín G. Zapata Agustín G. Zapata Juan A. Bueren Juan A. Bueren Juan A. Bueren Ángeles Vicente Ángeles Vicente Ángeles Vicente Fermín Sánchez-Guijo Fermín Sánchez-Guijo Fermín Sánchez-Guijo |
| author_sort | Jaris Valencia |
| collection | DOAJ |
| description | IntroductionMSCs exhibit regenerative, anti-inflammatory and immunomodulatory properties due to the large amount of cytokines, chemokines and growth factors they secrete. MSCs have been extensively evaluated in clinical trials, however, in some cases their therapeutic effects are variable. Therefore, strategies to improve their therapeutic potential, such as preconditioning with proinflammatory factors, have been proposed. Several priming approaches have provided non-conclusive results, and the duration of priming effects on MSC properties or their response to a second inflammatory stimulus have not been fully addressed.MethodsWe have investigated the impact of triple cytokine priming in MSCs on their characterization and viability, their transcriptomic profile, the functionality of innate and acquired immune cells, as well as the maintenance of the response to priming over time, their subsequent responsiveness to a second inflammatory stimulus.ResultsPriming MSCs with proinflammatory cytokines (CK-MSCs) do not modify the differentiation capacity of MSCs, nor their immunophenotype and viability. Moreover, cytokine priming enhances the anti-inflammatory and immunomodulatory properties of MSCs against NK and dendritic cells, while maintaining the same T cell immunomodulatory capacity as unstimulated MSCs. Thus, they decrease T-lymphocytes and NK cell proliferation, inhibit the differentiation and allostimulatory capacity of dendritic cells and promote the differentiation of monocytes with an immunosuppressive profile. In addition, we have shown for the first time that proinflammatory priming reduces the variability between different donors and MSC origins. Finally, the effect on CK-MSC is maintained over time and even after a secondary inflammatory stimulus.ConclusionsCytokine-priming improves the therapeutic potential of MSCs and reduces inter-donor variability. |
| format | Article |
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| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Frontiers in Immunology |
| spelling | doaj-art-bedd3ac2bc65426b8c04428a3757bdf32025-08-20T03:01:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.14737881473788Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacityJaris Valencia0Jaris Valencia1Jaris Valencia2Rosa M. Yáñez3Rosa M. Yáñez4Rosa M. Yáñez5Sandra Muntión6Sandra Muntión7Sandra Muntión8María Fernández-García9María Fernández-García10María Fernández-García11Jorge Diego Martín-Rufino12Jorge Diego Martín-Rufino13Agustín G. Zapata14Agustín G. Zapata15Agustín G. Zapata16Juan A. Bueren17Juan A. Bueren18Juan A. Bueren19Ángeles Vicente20Ángeles Vicente21Ángeles Vicente22Fermín Sánchez-Guijo23Fermín Sánchez-Guijo24Fermín Sánchez-Guijo25Department of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, SpainHeath Research Institute Hospital Clínico San Carlos (IdISSC), Madrid, SpainRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, SpainRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, SpainHematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainHeath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, SpainRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, SpainDepartment of Medicine, University of Salamanca and Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, Salamanca, SpainRegenerative Medicine and Cellular Therapy Network Center of Castilla y León, Salamanca, SpainRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, SpainHematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainHeath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, SpainDivision of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United StatesBroad Institute of MIT and Harvard, Cambridge, MA, United StatesRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain0Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain1Heath Research Institute Hospital 12 de Octubre (I+12), Madrid, SpainRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, SpainHematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainHeath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, SpainDepartment of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, SpainRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain1Heath Research Institute Hospital 12 de Octubre (I+12), Madrid, SpainRICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, SpainDepartment of Medicine, University of Salamanca and Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, Salamanca, SpainRegenerative Medicine and Cellular Therapy Network Center of Castilla y León, Salamanca, SpainIntroductionMSCs exhibit regenerative, anti-inflammatory and immunomodulatory properties due to the large amount of cytokines, chemokines and growth factors they secrete. MSCs have been extensively evaluated in clinical trials, however, in some cases their therapeutic effects are variable. Therefore, strategies to improve their therapeutic potential, such as preconditioning with proinflammatory factors, have been proposed. Several priming approaches have provided non-conclusive results, and the duration of priming effects on MSC properties or their response to a second inflammatory stimulus have not been fully addressed.MethodsWe have investigated the impact of triple cytokine priming in MSCs on their characterization and viability, their transcriptomic profile, the functionality of innate and acquired immune cells, as well as the maintenance of the response to priming over time, their subsequent responsiveness to a second inflammatory stimulus.ResultsPriming MSCs with proinflammatory cytokines (CK-MSCs) do not modify the differentiation capacity of MSCs, nor their immunophenotype and viability. Moreover, cytokine priming enhances the anti-inflammatory and immunomodulatory properties of MSCs against NK and dendritic cells, while maintaining the same T cell immunomodulatory capacity as unstimulated MSCs. Thus, they decrease T-lymphocytes and NK cell proliferation, inhibit the differentiation and allostimulatory capacity of dendritic cells and promote the differentiation of monocytes with an immunosuppressive profile. In addition, we have shown for the first time that proinflammatory priming reduces the variability between different donors and MSC origins. Finally, the effect on CK-MSC is maintained over time and even after a secondary inflammatory stimulus.ConclusionsCytokine-priming improves the therapeutic potential of MSCs and reduces inter-donor variability.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1473788/fullmesenchymal stem cellsmesenchymal stromal cellsMSCscytokinesprimingheterogeneity |
| spellingShingle | Jaris Valencia Jaris Valencia Jaris Valencia Rosa M. Yáñez Rosa M. Yáñez Rosa M. Yáñez Sandra Muntión Sandra Muntión Sandra Muntión María Fernández-García María Fernández-García María Fernández-García Jorge Diego Martín-Rufino Jorge Diego Martín-Rufino Agustín G. Zapata Agustín G. Zapata Agustín G. Zapata Juan A. Bueren Juan A. Bueren Juan A. Bueren Ángeles Vicente Ángeles Vicente Ángeles Vicente Fermín Sánchez-Guijo Fermín Sánchez-Guijo Fermín Sánchez-Guijo Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity Frontiers in Immunology mesenchymal stem cells mesenchymal stromal cells MSCs cytokines priming heterogeneity |
| title | Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity |
| title_full | Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity |
| title_fullStr | Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity |
| title_full_unstemmed | Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity |
| title_short | Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity |
| title_sort | improving the therapeutic profile of mscs cytokine priming reduces donor dependent heterogeneity and enhances their immunomodulatory capacity |
| topic | mesenchymal stem cells mesenchymal stromal cells MSCs cytokines priming heterogeneity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1473788/full |
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