| Author | Ferro, Zaquer Suzana Munhoz Costa | |
| Author | Rocha, Gisele Vieira | |
| Author | Silva, Katia Nunes da | |
| Author | Paredes, Bruno Diaz | |
| Author | Loiola, Erick Correia | |
| Author | Silva, Johnatas Dutra | |
| Author | Santos, John Lenon de Souza | |
| Author | Dias, Rosane Borges | |
| Author | Figueira, Cláudio Pereira | |
| Author | Oliveira, Camila Indiani de | |
| Author | Moura, Ludmilla David de | |
| Author | Ribeiro, Lígia Nunes de Morais | |
| Author | Paula, Eneida de | |
| Author | Zanette, Dalila Lucíola | |
| Author | Rocha, Clarissa Araújo Gurgel | |
| Author | Rocco, Patricia Rieken Macedo | |
| Author | Souza, Bruno Solano de Freitas | |
| Access date | 2024-05-17T17:09:45Z | |
| Available date | 2024-05-17T17:09:45Z | |
| Document date | 2024 | |
| Citation | FERRO, Zaquer Suzana Munhoz Costa et al. GMP-compliant extracellular vesicles derived from umbilical cord mesenchymal stromal cells: manufacturing and preclinical evaluation in ARDS treatment. Cytotherapy, v. 26, n. 5, p. 1-37, 2024. | en_US |
| ISSN | 1477-2566 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/64121 | |
| Sponsorship | Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).
Ministério da Saúde, Departamento de Ciência e Tecnologia (DECIT).
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
Instituto Nacional de Ciência e Tecnologia de Medicina Regenerativa.
Instituto D'OR Pesquisa e Ensino.
Fundação Maria Emília. | en_US |
| Language | eng | en_US |
| Publisher | Elsevier | en_US |
| Rights | open access | |
| Subject in Portuguese | ARDS | en_US |
| Subject in Portuguese | Biodistribuição | en_US |
| Subject in Portuguese | Vesículas extracelulares | en_US |
| Subject in Portuguese | Células estromais mesenquimais ade | en_US |
| Subject in Portuguese | Pré-clínico | en_US |
| Subject in Portuguese | Proteômica | en_US |
| Subject in Portuguese | Toxicidade | en_US |
| Title | GMP-compliant extracellular vesicles derived from umbilical cord mesenchymal stromal cells: manufacturing and preclinical evaluation in ARDS treatment | en_US |
| Type | Article | |
| DOI | 10.1016/j.jcyt.2024.04.074 | |
| Abstract | Background aims: Extracellular vesicles (EVs) represent a new axis of intercellular communication that can be harnessed for therapeutic purposes, as cell-free therapies. The clinical application of mesenchymal stromal cell (MSC)-derived EVs, however, is still in its infancy and faces many challenges. The heterogeneity inherent to MSCs, differences among donors, tissue sources, and variations in manufacturing conditions may influence the release of EVs and their cargo, thus potentially affecting the quality and consistency of the final product. We investigated the influence of cell culture and conditioned medium harvesting conditions on the physicochemical and proteomic profile of human umbilical cord MSC-derived EVs (hUCMSC-EVs) produced under current good manufacturing practice (cGMP) standards. We also evaluated the efficiency of the protocol in terms of yield, purity, productivity, and expression of surface markers, and assessed the biodistribution, toxicity and potential efficacy of hUCMSC-EVs in pre-clinical studies using the LPS-induced acute lung injury model. Methods: hUCMSCs were isolated from a cord tissue, cultured, cryopreserved, and characterized at a cGMP facility. The conditioned medium was harvested at 24, 48, and 72 h after the addition of EV collection medium. Three conventional methods (nanoparticle tracking analysis, transmission electron microscopy, and nanoflow cytometry) and mass spectrometry were used to characterize hUCMSC-EVs. Safety (toxicity of single and repeated doses) and biodistribution were evaluated in naive mice after intravenous administration of the product. Efficacy was evaluated in an LPS-induced acute lung injury model. Results: hUCMSC-EVs were successfully isolated using a cGMP-compliant protocol. Comparison of hUCMSC-EVs purified from multiple harvests revealed progressive EV productivity and slight changes in the proteomic profile, presenting higher homogeneity at later timepoints of conditioned medium harvesting. Pooled hUCMSC-EVs showed a non-toxic profile after single and repeated intravenous administration to naive mice. Biodistribution studies demonstrated a major concentration in liver, spleen and lungs. HUCMSC-EVs reduced lung damage and inflammation in a model of LPS-induced acute lung injury. Conclusions:
hUCMSC-EVs were successfully obtained following a cGMP-compliant protocol, with consistent characteristics and pre-clinical safety profile, supporting their future clinical development as cell-free therapies. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Instituto D'Or de Pesquisa e Ensino (IDOR). Salvador, BA, Brasil. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Instituto D'Or de Pesquisa e Ensino (IDOR). Salvador, BA, Brasil. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Instituto D'Or de Pesquisa e Ensino (IDOR). Salvador, BA, Brasil. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Instituto D'Or de Pesquisa e Ensino (IDOR). Salvador, BA, Brasil. | en_US |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Ciência e Tecnologia de Medicina Regenerativa. Rio de Janeiro, RJ, Brasil / Rede Rio de Janeiro de Inovação em Nanossistemas para Saúde-NanoSaúde. Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Salvador, BA, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
| Affilliation | Universidade Estadual de Campinas. Instituto de Biologia. Campinas, SP, Brasil. | en_US |
| Affilliation | Universidade Estadual de Campinas. Instituto de Biologia. Campinas, SP, Brasil / Universidade Federal de Uberlândia. Instituto de Biotecnologia. Uberlândia, MG, Brasil. | en_US |
| Affilliation | Universidade Estadual de Campinas. Instituto de Biologia. Campinas, SP, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Universidade Federal da Bahia. Salvador, BA, Brasil. | en_US |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Ciência e Tecnologia de Medicina Regenerativa. Rio de Janeiro, RJ, Brasil / Rede Rio de Janeiro de Inovação em Nanossistemas para Saúde-NanoSaúde. Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
| Subject | ARDS | en_US |
| Subject | Biodistribution | en_US |
| Subject | Extracellular vesicles | en_US |
| Subject | Mesenchymal stromal cells | en_US |
| Subject | Pre-clinical | en_US |
| Subject | Proteomics | en_US |
| Subject | Toxicity | en_US |
| DeCS | Síndrome do desconforto respiratório | en_US |
| DeCS | Vesículas extracelulares | en_US |
| DeCS | Células estromais | en_US |
| DeCS | Proteômica | en_US |
| DeCS | Toxicidade | en_US |
