Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?

Bibliographic Details
Main Author: Faria, Helena Maria Vilaça
Publication Date: 2019
Format: Master thesis
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: https://hdl.handle.net/1822/81886
Summary: Dissertação de mestrado em Ciências da Saúde
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network_name_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
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spelling Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?Doença de ParkinsonCélulas estaminais mesenquimatosasSecretomaExossomasParkinson’s diseaseMesenchymal stem cellsSecretomeExosomesCiências Médicas::Ciências da SaúdeDissertação de mestrado em Ciências da SaúdeA doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum no mundo. É caracterizada clinicamente por complicações motoras severas causadas pela degeneração progressiva de neurónios dopaminérgicos (DAn) e pelo declínio de dopamina. Os tratamentos atuais focam-se no uso de estratégias farmacológicas como a administração de levodopa, focando se apenas na atenuação dos sintomas motores e não na regeneração dos DAn. Portanto, o desenvolvimento de estratégias regenerativas é essencial, as quais podem levar a ganhos promissores na investigação translacional da DP. O secretoma de células estaminais mesenquimatosas humanas (hMSCs) tem sido proposto como uma ferramenta terapêutica promissora para a DP, dado a sua capacidade de modular a sobrevivência de DAn. Enquanto que com a fração proteica, o nosso laboratório já identificou proteínas promissoras com ações terapêuticas na DP, levando a melhorias histológicas e comportamentais, o potencial da sua fração vesicular/exossomal ainda permanece pouco explorada. As vesículas derivadas das hMSCs são capazes de atuar como nanopartículas biológicas com efeitos benéficos em diferentes condições patológicas, incluindo na DP. Assim sendo, o objetivo deste trabalho foi isolar e caracterizar os exossomas derivados do secretoma de hMSCs, assim como avaliar o seu impacto na sobrevivência, e na diferenciação neuronal através do uso de modelos in vitro e in vivo da DP. Os resultados demonstraram que foi possível o isolamento de exossomas por um protocolo de ultracentrifugação diferencial, ao caracterizar as amostras através da técnica Dynamic Light Scattering (DLS). Adicionalmente, ensaios in vitro, com o objetivo de avaliar a diferenciação neuronal para marcadores DCX e MAP-2, revelaram que a fração exossomal foi capaz de induzir diferenciação de células progenitoras neurais (NPCs) ao mesmo nível que o secretoma total, enquanto que a fração proteica não foi capaz de induzir tal efeito. Num modelo de DP de 6-OHDA, foi possível observar que as diferentes frações do secretoma induziram um efeito positivo na performance motora e na análise histológica, apesar de apresentarem efeitos distintos, indicando assim que o secretoma e as suas diferentes frações podem influenciar diferentes mecanismos e vias. Em suma, é possível concluir que o secretoma de hMSCs e as suas frações podem ser moduladores de diferentes mecanismos de neuroregeneração, abrindo uma oportunidade para o seu uso como estratégia terapêutica no tratamento da DP.Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disorder in the world. It is clinically characterized by severe motor complications caused by the progressive degeneration of dopaminergic neurons (DAn) and dopamine loss. Current treatment focus on mitigating the symptoms through levodopa administration, rather than preventing DAn damage. Therefore, the development of regenerative strategies is essential, which can lead to promising gains on PD translational research. Human mesenchymal stem cells (hMSCs) secretome has been proposed as a promising therapeutic tool, given their ability to modulate DAn survival. While with the protein fraction, our lab has already identified promising proteins with therapeutic actions on PD, leading to histological and behavioral improvements, the potential of its vesicular/exosomal fraction still remains not fully understood. hMSCs – derived vesicles are able to act as biological nanoparticles with beneficial effects in different pathological conditions, including PD. Therefore, the aim of this work was to isolate hMSCs secretome-derived exosomes and characterize its fraction, as well as assess their impact on neuronal survival, and differentiation through the use of in vitro and in in vivo models of PD. Our results have demonstrated that we were able to isolate hMSCs-derived exosomes by a differential ultracentrifugation protocol, when characterizing exosomal samples through Dynamic Light Scattering (DLS) method. Concerning in vitro assays assessing neuronal differentiation to DCX and MAP-2 markers, results revealed that the exosomal fraction was able to induce neural progenitor cells (NPCs) differentiation at the same levels as the whole secretome, while the protein separated fraction was not able to induce such effect. In a 6-OHDA rat model of PD, we have observed that hBM-MSCs secretome and its derived fractions displayed a positive impact on animals’ motor and histological performance, although presenting distinct effects, thereby indicating that the secretome and its different fractions may impact different mechanisms and pathways. Overall, we concluded that the use of the secretome collected from hBM-MSCs and its different fractions might be active modulators of different neuroregeneration mechanisms, opening a door for their future use as therapeutical strategies in the treatment of PD.This work was supported by the Portuguese Foundation for Science and Technology (FCT): IF Development Grant (IF/00111/2013) to AJ Salgado and Post-Doctoral Fellowship to FG Teixeira (SFRH/BPD/118408/2016). This work was funded by FEDER, through the Competitiveness Internationalization Operational Programme (POCI), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-029751. This article has also been developed under the scope of the project NORTE-01-0145-FEDER 000023, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through FCT, under the scope of the project POCI-01-0145-FEDER-007038.Teixeira, Fábio Gabriel RodriguesSalgado, A. J.Universidade do MinhoFaria, Helena Maria Vilaça2019-07-222019-07-22T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttps://hdl.handle.net/1822/81886eng202441733info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2024-05-11T04:36:26Zoai:repositorium.sdum.uminho.pt:1822/81886Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-28T14:53:15.839182Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
title Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
spellingShingle Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
Faria, Helena Maria Vilaça
Doença de Parkinson
Células estaminais mesenquimatosas
Secretoma
Exossomas
Parkinson’s disease
Mesenchymal stem cells
Secretome
Exosomes
Ciências Médicas::Ciências da Saúde
title_short Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
title_full Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
title_fullStr Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
title_full_unstemmed Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
title_sort Mesenchymal stem cells secretome – derived exosomes: biological nanovesicles for the treatment of Parkinson’s Disease?
author Faria, Helena Maria Vilaça
author_facet Faria, Helena Maria Vilaça
author_role author
dc.contributor.none.fl_str_mv Teixeira, Fábio Gabriel Rodrigues
Salgado, A. J.
Universidade do Minho
dc.contributor.author.fl_str_mv Faria, Helena Maria Vilaça
dc.subject.por.fl_str_mv Doença de Parkinson
Células estaminais mesenquimatosas
Secretoma
Exossomas
Parkinson’s disease
Mesenchymal stem cells
Secretome
Exosomes
Ciências Médicas::Ciências da Saúde
topic Doença de Parkinson
Células estaminais mesenquimatosas
Secretoma
Exossomas
Parkinson’s disease
Mesenchymal stem cells
Secretome
Exosomes
Ciências Médicas::Ciências da Saúde
description Dissertação de mestrado em Ciências da Saúde
publishDate 2019
dc.date.none.fl_str_mv 2019-07-22
2019-07-22T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://hdl.handle.net/1822/81886
url https://hdl.handle.net/1822/81886
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 202441733
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
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instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
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reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
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