Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles

Detalhes bibliográficos
Autor(a) principal: Rodrigues, Sílvia C.
Data de Publicação: 2021
Outros Autores: Cardoso, Renato M. S., Gomes, Claudia F., Duarte, Filipe Valente, Freire, Patricia C., Neves, Ricardo, Correia, Joana Simões
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/105226
https://doi.org/10.3390/membranes11090647
Resumo: The development and adoption of cell therapies has been largely limited by difficulties associated with their safety, handling, and storage. Extracellular vesicles (EV) have recently emerged as a likely mediator for the therapeutic effect of cells, offering several advantages over cell therapies. Due to their small size and inability to expand and metastasize, EV are generally considered safer than cell transplantation. Nevertheless, few studies have scrutinized the toxicity profile of EV, particularly after repeated high-dose administration. The present study aimed to evaluate a preparation of small EV obtained from umbilical cord blood mononuclear cells (UCB-MNC-sEV) for its cytotoxicity in different cell lines, as well as its differential accumulation, distribution, and toxicity following repeated intravenous (IV) administrations in a rodent model. In vitro, repeated sEV exposure in concentrations up to 1 × 1011 particles/mL had no deleterious impact on the viability or metabolic activity of peripheral blood mononuclear cells, THP-1 monocytes, THP-1-derived macrophages, normal dermal human fibroblasts, or human umbilical vein endothelial cells. DiR-labelled sEV, injected intravenously for four weeks in healthy rats, were detected in clearance organs, particularly the kidneys, spleen, and liver, similarly to control dye. Moreover, repeated administrations for six and twelve weeks of up to 1 × 1010 total particles of sEV dye were well-tolerated, with no changes in general haematological cell counts, or kidney and liver toxicity markers. More importantly, unlabelled sEV likewise did not induce significant alterations in cellular and biochemical blood parameters, nor any morphological changes in the heart, kidney, lung, spleen, or liver tissue. In sum, our data show that UCB-MNC-sEV have no significant toxicity in vitro or in vivo, even when administered repeatedly at high concentrations, therefore confirming their safety profile and potential suitability for future clinical use.
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spelling Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesiclesextracellular vesiclesumbilical cord bloodEV therapeuticsEV toxicityThe development and adoption of cell therapies has been largely limited by difficulties associated with their safety, handling, and storage. Extracellular vesicles (EV) have recently emerged as a likely mediator for the therapeutic effect of cells, offering several advantages over cell therapies. Due to their small size and inability to expand and metastasize, EV are generally considered safer than cell transplantation. Nevertheless, few studies have scrutinized the toxicity profile of EV, particularly after repeated high-dose administration. The present study aimed to evaluate a preparation of small EV obtained from umbilical cord blood mononuclear cells (UCB-MNC-sEV) for its cytotoxicity in different cell lines, as well as its differential accumulation, distribution, and toxicity following repeated intravenous (IV) administrations in a rodent model. In vitro, repeated sEV exposure in concentrations up to 1 × 1011 particles/mL had no deleterious impact on the viability or metabolic activity of peripheral blood mononuclear cells, THP-1 monocytes, THP-1-derived macrophages, normal dermal human fibroblasts, or human umbilical vein endothelial cells. DiR-labelled sEV, injected intravenously for four weeks in healthy rats, were detected in clearance organs, particularly the kidneys, spleen, and liver, similarly to control dye. Moreover, repeated administrations for six and twelve weeks of up to 1 × 1010 total particles of sEV dye were well-tolerated, with no changes in general haematological cell counts, or kidney and liver toxicity markers. More importantly, unlabelled sEV likewise did not induce significant alterations in cellular and biochemical blood parameters, nor any morphological changes in the heart, kidney, lung, spleen, or liver tissue. In sum, our data show that UCB-MNC-sEV have no significant toxicity in vitro or in vivo, even when administered repeatedly at high concentrations, therefore confirming their safety profile and potential suitability for future clinical use.MDPI2021-08-24info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/105226http://hdl.handle.net/10316/105226https://doi.org/10.3390/membranes11090647eng2077-0375Rodrigues, Sílvia C.Cardoso, Renato M. S.Gomes, Claudia F.Duarte, Filipe ValenteFreire, Patricia C.Neves, RicardoCorreia, Joana Simõesinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-02-09T13:27:29Zoai:estudogeral.uc.pt:10316/105226Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:21:49.697055Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
title Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
spellingShingle Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
Rodrigues, Sílvia C.
extracellular vesicles
umbilical cord blood
EV therapeutics
EV toxicity
title_short Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
title_full Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
title_fullStr Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
title_full_unstemmed Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
title_sort Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles
author Rodrigues, Sílvia C.
author_facet Rodrigues, Sílvia C.
Cardoso, Renato M. S.
Gomes, Claudia F.
Duarte, Filipe Valente
Freire, Patricia C.
Neves, Ricardo
Correia, Joana Simões
author_role author
author2 Cardoso, Renato M. S.
Gomes, Claudia F.
Duarte, Filipe Valente
Freire, Patricia C.
Neves, Ricardo
Correia, Joana Simões
author2_role author
author
author
author
author
author
dc.contributor.author.fl_str_mv Rodrigues, Sílvia C.
Cardoso, Renato M. S.
Gomes, Claudia F.
Duarte, Filipe Valente
Freire, Patricia C.
Neves, Ricardo
Correia, Joana Simões
dc.subject.por.fl_str_mv extracellular vesicles
umbilical cord blood
EV therapeutics
EV toxicity
topic extracellular vesicles
umbilical cord blood
EV therapeutics
EV toxicity
description The development and adoption of cell therapies has been largely limited by difficulties associated with their safety, handling, and storage. Extracellular vesicles (EV) have recently emerged as a likely mediator for the therapeutic effect of cells, offering several advantages over cell therapies. Due to their small size and inability to expand and metastasize, EV are generally considered safer than cell transplantation. Nevertheless, few studies have scrutinized the toxicity profile of EV, particularly after repeated high-dose administration. The present study aimed to evaluate a preparation of small EV obtained from umbilical cord blood mononuclear cells (UCB-MNC-sEV) for its cytotoxicity in different cell lines, as well as its differential accumulation, distribution, and toxicity following repeated intravenous (IV) administrations in a rodent model. In vitro, repeated sEV exposure in concentrations up to 1 × 1011 particles/mL had no deleterious impact on the viability or metabolic activity of peripheral blood mononuclear cells, THP-1 monocytes, THP-1-derived macrophages, normal dermal human fibroblasts, or human umbilical vein endothelial cells. DiR-labelled sEV, injected intravenously for four weeks in healthy rats, were detected in clearance organs, particularly the kidneys, spleen, and liver, similarly to control dye. Moreover, repeated administrations for six and twelve weeks of up to 1 × 1010 total particles of sEV dye were well-tolerated, with no changes in general haematological cell counts, or kidney and liver toxicity markers. More importantly, unlabelled sEV likewise did not induce significant alterations in cellular and biochemical blood parameters, nor any morphological changes in the heart, kidney, lung, spleen, or liver tissue. In sum, our data show that UCB-MNC-sEV have no significant toxicity in vitro or in vivo, even when administered repeatedly at high concentrations, therefore confirming their safety profile and potential suitability for future clinical use.
publishDate 2021
dc.date.none.fl_str_mv 2021-08-24
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/105226
http://hdl.handle.net/10316/105226
https://doi.org/10.3390/membranes11090647
url http://hdl.handle.net/10316/105226
https://doi.org/10.3390/membranes11090647
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