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3D-MSCs A151 ODN-Loaded Exosomes Are Immunomodulatory And Reveal A Proteomic Cargo That Sustains Wound Resolution

2022-01Journal article Open access
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dc.contributor.authorP Camões, Sérgio
dc.contributor.authorBulut, Ozlem
dc.contributor.authorYazar, Volkan
dc.contributor.authorGaspar, Maria Manuela
dc.contributor.authorSimões, Sandra
dc.contributor.authorFerreira, Rita
dc.contributor.authorVitorino, Rui
dc.contributor.authorSantos, Jorge M.
dc.contributor.authorGursel, Ihsan
dc.contributor.authorMiranda, Joana P
dc.date.accessioned2022-04-12T14:01:55Z
dc.date.available2022-04-12T14:01:55Z
dc.date.issued2022-01
dc.date.updated2022-02-24T12:13:51Z
dc.description.abstractIntroduction Non-healing wounds remain a major burden due to the lack of effective treatments. Mesenchymal stem cell-derived exosomes (MSC-Exo) have emerged as therapeutic options given their pro-regenerative and immunomodulatory features. Still, little is known on the exact mechanisms mediated by MSC-Exo. Importantly, modulation of their efficacy through 3D-physiologic cultures together with loading strategies continues underexplored. Objectives To uncover the MSC-Exo-mediated mechanism via proteomic analyses, and to use 3D-culture and loading technologies to expand MSC-Exo efficacy for cutaneous wound healing. Methods MSC-Exo were produced in either 3D or 2D cultures (Exo3D/Exo2D) and loaded with an exogenous immunosuppressive oligodeoxynucleotide (A151 ODN). Both, loaded and naïve exosomes were characterised regarding size, morphology and the presence of specific protein markers; while IPA analyses enabled to correlate their protein content with the effects observed in vitro and in vivo. The Exo3D/Exo2D regenerative potential was evaluated in vitro by assessing keratinocyte and fibroblast mitogenicity, motogenicity, and cytokine secretion as well as using an in vivo wound splinting model. Accordingly, the modulation of inflammatory and immune responses by A151-loaded Exo3D/Exo2D was also assessed. Results Exo3D stimulated mitogenically and motogenically keratinocytes and fibroblasts in vitro, with upregulation of IL-1α and VEGF-α or increased secretion of TGF-β, TNF-α and IL-10. In vivo, Exo3D reduced the granulation tissue area and promoted complete re-epithelization of the wound. These observations were sustained by the proteomic profiling of the Exo3D cargo that identified wound healing-related proteins, such as TGF-β, ITGA1-3/5, IL-6, CDC151, S100A10 and Wnt5α. Moreover, when loaded with A151 ODN, Exo3D differentially mediated wound healing-related trophic factors reducing the systemic levels of IL-6 and TNF-α at the late stage of wound healing in vivo. Conclusion Our results support the potential of A151-loaded Exo3D for the treatment of chronic wounds by promoting skin regeneration, while modulating the systemic levels of the pro-inflammatory cytokinespt_PT
dc.description.sponsorshipThis study was partially supported by FCT (PTDC/MED-TOX/29183/2017, PTDC/MED-QUI/31721/2017 and PTDC/SAU-SER/30197/2017), by strategic funding for iMed.ULisboa (UIDB/04138/2020 and UIDP/04138/2020), for UnIC (UID/00051/2020) and for iBiMED (UID/BIM/04501/2020), and by European Union, Quadro de Referência Estratégico Nacional (QREN), Fundo Europeu de Desenvolvimento Regional (FEDER) and Programa Operacional Fatores de Competitividade (COMPETE) (POCI-01-0145-FEDER-007628 and LISBOA-01-0145- FEDER-030197). VIB Proteomics Core and COST Actions (EU Framework Programme Horizon 2020) CA16113 and CA16119 are also acknowledged. The authors thank Dr. Tânia Carvalho for her valuable assistance on histological analysis. SPC also acknowledges EFIS-IL short-term fellowship.pt_PT
dc.description.versioninfo:eu-repo/semantics/acceptedVersionpt_PT
dc.identifier.citationCamões SP, Bulut O, Yazar V, Gaspar MM, Simões S, Ferreira R, et al. 3D-MSCs A151 ODN-loaded exosomes are immunomodulatory and reveal a proteomic cargo that sustains wound resolution. Journal of Advanced Research [Internet]. 2022;S2090123222000261. Disponível em: https://linkinghub.elsevier.com/retrieve/pii/S2090123222000261pt_PT
dc.identifier.doihttps://doi.org/10.1016/j.jare.2022.01.013pt_PT
dc.identifier.issn2090-1232
dc.identifier.slugcv-prod-2694205
dc.identifier.urihttp://hdl.handle.net/10451/52308
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationTUBITAK/003/2014pt_PT
dc.relationUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
dc.relationResearch Institute for Medicines
dc.relationNANOFORMULATED HYBRID MOLECULES FOR SPECIFIC TAREGETING MELANOMA METASTASIS
dc.relationSustainable, Safe, and Scalable (3S) approach for lycopene valorization: driving the knowledge toward an academia-industry interface for topical treatment of inflammation
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationPOCI-01-0145-FEDER-007628pt_PT
dc.relationLISBOA-01-0145- FEDER-030197pt_PT
dc.relation.publisherversionhttps://doi.org/10.1016/j.jare.2022.01.013pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectExosomespt_PT
dc.subjectImmunosuppressive oligodeoxynucleotide loadingpt_PT
dc.subjectImmunomodulationpt_PT
dc.subjectProteomicspt_PT
dc.subject3D-cultured mesenchymal stem/stromal cellspt_PT
dc.subjectWound healingpt_PT
dc.title3D-MSCs A151 ODN-Loaded Exosomes Are Immunomodulatory And Reveal A Proteomic Cargo That Sustains Wound Resolutionpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
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oaire.awardTitleNANOFORMULATED HYBRID MOLECULES FOR SPECIFIC TAREGETING MELANOMA METASTASIS
oaire.awardTitleSustainable, Safe, and Scalable (3S) approach for lycopene valorization: driving the knowledge toward an academia-industry interface for topical treatment of inflammation
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oaire.citation.titleJournal of Advanced Researchpt_PT
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person.familyNameP Camões
person.familyNamede Jesus Guilherme Gaspar
person.familyNameSimões
person.familyNameMiranda
person.givenNameSérgio
person.givenNameMaria Manuela
person.givenNameSandra
person.givenNameJoana P G
person.identifierC-2024-2014
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person.identifier.orcid0000-0003-0355-5338
person.identifier.orcid0000-0001-6814-7226
person.identifier.orcid0000-0002-5685-1790
person.identifier.orcid0000-0002-7804-4068
person.identifier.ridJ-3698-2013
person.identifier.scopus-author-id15834627800
person.identifier.scopus-author-id8724939200
person.identifier.scopus-author-id12798235300
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
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project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.cv.cienciaid001A-6278-C231 | Joana Paiva Gomes Miranda
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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