Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.6/13897 |
Resumo: | Neonatal Hypoxic-Ischemic Encephalopathy (HIE) is one of the most serious complications occurring during the perinatal period and is considered one of the leading causes of neonatal death and long-term disability. Although data differ among the literature, it is believed that about 1.5 in 1000 term births are affected in developed countries and that about 26 in 1000 births are affected in developing countries. Currently, the only therapy in clinical use for the treatment of HIE is the therapeutic hypothermia, however, it is only partially effective. Many of the emerging neuroprotective strategies that are being studied for the treatment of HIE are focused on mitigating the effects on the brain of the secondary energy failure, however, some are used in combination with therapeutic hypothermia and still present several limitations for their clinical translation. Recent studies point out mesenchymal stem cells (MSCs) as a possible therapy for HIE however, several studies have revealed limitations in their use. Moreover, it is now known that the positive impact resulting from MSCs administration is not only attributed to their migration to injured sites and differentiation but primarily to their paracrine activity. This paradigm shift towards paracrine signaling has raised interest in the potential of MSCs' conditioned medium to overcome some limitations imposed by cell therapy. Therefore, to evaluate the therapeutic potential of the intranasal administration of the secretome from umbilical cord (UC)-MSCs, a hypoxic-ischemic brain lesion was induced in rat pups and secretome administrations were performed two- and three-days post-injury. Several behavioral tests were performed in the following days to assess the impact of this strategy on cognitive and motor functions. In order to complement the results obtained, an analysis of the lesion size was carried out in all the experimental groups. Intranasal administration of UC-MSCs secretome improved sensorimotor, animal’s gait, motor coordination and recognition memory impairments observed after neonatal hypoxic-ischemic brain injury at different stages of development. However, it was not possible to draw any conclusions about its impact on spatial memory and balance impairments. Moreover, the neonatal hypoxic-ischemic injury led to a brain lesion involving about 22% of the left hemisphere that was reduced to 10% with the secretome treatment. Despite its preliminary nature, the present work has shown that secretome administration positively impacted several functional parameters known to be affected by HIE, as well as in the recovery of the volume of injured tissue. Nonetheless, more studies need to be conducted to strengthen these conclusions. |
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Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic EncephalopathyAdministração IntranasalCélulas Estaminais MesenquimaisEncefalopatia Hipóxico IsquémicaSecretomaDomínio/Área Científica::Ciências Médicas::Ciências BiomédicasNeonatal Hypoxic-Ischemic Encephalopathy (HIE) is one of the most serious complications occurring during the perinatal period and is considered one of the leading causes of neonatal death and long-term disability. Although data differ among the literature, it is believed that about 1.5 in 1000 term births are affected in developed countries and that about 26 in 1000 births are affected in developing countries. Currently, the only therapy in clinical use for the treatment of HIE is the therapeutic hypothermia, however, it is only partially effective. Many of the emerging neuroprotective strategies that are being studied for the treatment of HIE are focused on mitigating the effects on the brain of the secondary energy failure, however, some are used in combination with therapeutic hypothermia and still present several limitations for their clinical translation. Recent studies point out mesenchymal stem cells (MSCs) as a possible therapy for HIE however, several studies have revealed limitations in their use. Moreover, it is now known that the positive impact resulting from MSCs administration is not only attributed to their migration to injured sites and differentiation but primarily to their paracrine activity. This paradigm shift towards paracrine signaling has raised interest in the potential of MSCs' conditioned medium to overcome some limitations imposed by cell therapy. Therefore, to evaluate the therapeutic potential of the intranasal administration of the secretome from umbilical cord (UC)-MSCs, a hypoxic-ischemic brain lesion was induced in rat pups and secretome administrations were performed two- and three-days post-injury. Several behavioral tests were performed in the following days to assess the impact of this strategy on cognitive and motor functions. In order to complement the results obtained, an analysis of the lesion size was carried out in all the experimental groups. Intranasal administration of UC-MSCs secretome improved sensorimotor, animal’s gait, motor coordination and recognition memory impairments observed after neonatal hypoxic-ischemic brain injury at different stages of development. However, it was not possible to draw any conclusions about its impact on spatial memory and balance impairments. Moreover, the neonatal hypoxic-ischemic injury led to a brain lesion involving about 22% of the left hemisphere that was reduced to 10% with the secretome treatment. Despite its preliminary nature, the present work has shown that secretome administration positively impacted several functional parameters known to be affected by HIE, as well as in the recovery of the volume of injured tissue. Nonetheless, more studies need to be conducted to strengthen these conclusions.A Encefalopatia Hipóxico-Isquémica Neonatal (HIE, do inglês Hypoxic Ischemic Encephalopathy) é uma das complicações mais graves que ocorrem durante o período perinatal e é considerada uma das principais causas de morte neonatal e de incapacidade a longo prazo. Embora haja divergência nos dados da literatura, acreditase que ocorre em cerca de 1,5 a cada 1000 nascimentos a termo nos países desenvolvidos e em cerca de 26 a cada 1000 nos países em desenvolvimento. Atualmente, a única terapia em uso clínico para o tratamento específico da HIE é a hipotermia terapêutica, no entanto é apenas parcialmente eficaz e apresenta várias limitações. Muitas das estratégias neuroprotetoras emergentes que estão a ser estudadas para o tratamento da HIE, centram-se principalmente na atenuação dos efeitos causados no cérebro pela falha de energia secundária, contudo, muitas são utilizadas em combinação com a hipotermia terapêutica e/ou apresentam várias limitações para a sua translação clínica. Estudos recentes apontam as células estaminais mesenquimais (MSCs, do inglês Mesenchymal Stem Cells) como uma possível terapia para a HIE, no entanto, vários estudos revelaram limitações na sua utilização. Além disso, sabe-se agora que o impacto positivo resultante da administração de MSCs não é apenas atribuído à sua migração para os locais lesionados e diferenciação, mas principalmente à sua atividade parácrina. Esta mudança de paradigma para a sinalização parácrina despertou o interesse no potencial do meio condicionado das MSCs para ultrapassar algumas limitações impostas pela terapia celular. Assim, para avaliar o potencial terapêutico da administração intranasal do secretoma das MSCs do cordão umbilical, foi induzida uma lesão cerebral hipóxico-isquémica em crias de rato e as administrações do secretoma foram realizadas dois e três dias após a lesão. Nos dias seguintes, foram efetuados vários testes comportamentais de forma a avaliar o impacto desta estratégia nas funções cognitivas e motoras dos animais. Com o intuito de complementar os resultados obtidos, foi também realizada uma análise da extensão da lesão em todos os grupos experimentais. A administração intranasal do secretoma do cordão umbilical demonstrou melhorar deficiências sensorimotoras, a marcha, a coordenação motora e a memória de reconhecimento observadas após a lesão neonatal hipóxico-isquémica, em diferentes fases de desenvolvimento. No entanto, não foi possível tirar conclusões do seu impacto a nível da memória espacial e do equilíbrio. Adicionalmente, a lesão hipóxicoisquémica neonatal provocou uma lesão cerebral que envolveu cerca de 22% do hemisfério esquerdo, sendo reduzida para aproximadamente 10% com a administração do secretoma. Apesar da sua natureza preliminar, o presente trabalho demonstrou que a administração do secretoma teve um impacto positivo em vários parâmetros funcionais afetados pela HIE tal como na recuperação do volume do tecido lesionado. No entanto, é necessário efetuar mais estudos para reforçar estas conclusões.Baltazar, Graça Maria FernandesSerrenho, Inês Isabel PiresuBibliorumSilva, Andreia Filipa Francisco Valente da2023-11-222023-10-092026-10-06T00:00:00Z2023-11-22T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10400.6/13897TID:203453999enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-01-17T03:47:39Zoai:ubibliorum.ubi.pt:10400.6/13897Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T01:45:01.078565Repositório 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 |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy |
title |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy |
spellingShingle |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy Silva, Andreia Filipa Francisco Valente da Administração Intranasal Células Estaminais Mesenquimais Encefalopatia Hipóxico Isquémica Secretoma Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
title_short |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy |
title_full |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy |
title_fullStr |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy |
title_full_unstemmed |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy |
title_sort |
Administration of MSCs Secretome as a Therapeutic Strategy for Neonatal Hypoxic Ischemic Encephalopathy |
author |
Silva, Andreia Filipa Francisco Valente da |
author_facet |
Silva, Andreia Filipa Francisco Valente da |
author_role |
author |
dc.contributor.none.fl_str_mv |
Baltazar, Graça Maria Fernandes Serrenho, Inês Isabel Pires uBibliorum |
dc.contributor.author.fl_str_mv |
Silva, Andreia Filipa Francisco Valente da |
dc.subject.por.fl_str_mv |
Administração Intranasal Células Estaminais Mesenquimais Encefalopatia Hipóxico Isquémica Secretoma Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
topic |
Administração Intranasal Células Estaminais Mesenquimais Encefalopatia Hipóxico Isquémica Secretoma Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
description |
Neonatal Hypoxic-Ischemic Encephalopathy (HIE) is one of the most serious complications occurring during the perinatal period and is considered one of the leading causes of neonatal death and long-term disability. Although data differ among the literature, it is believed that about 1.5 in 1000 term births are affected in developed countries and that about 26 in 1000 births are affected in developing countries. Currently, the only therapy in clinical use for the treatment of HIE is the therapeutic hypothermia, however, it is only partially effective. Many of the emerging neuroprotective strategies that are being studied for the treatment of HIE are focused on mitigating the effects on the brain of the secondary energy failure, however, some are used in combination with therapeutic hypothermia and still present several limitations for their clinical translation. Recent studies point out mesenchymal stem cells (MSCs) as a possible therapy for HIE however, several studies have revealed limitations in their use. Moreover, it is now known that the positive impact resulting from MSCs administration is not only attributed to their migration to injured sites and differentiation but primarily to their paracrine activity. This paradigm shift towards paracrine signaling has raised interest in the potential of MSCs' conditioned medium to overcome some limitations imposed by cell therapy. Therefore, to evaluate the therapeutic potential of the intranasal administration of the secretome from umbilical cord (UC)-MSCs, a hypoxic-ischemic brain lesion was induced in rat pups and secretome administrations were performed two- and three-days post-injury. Several behavioral tests were performed in the following days to assess the impact of this strategy on cognitive and motor functions. In order to complement the results obtained, an analysis of the lesion size was carried out in all the experimental groups. Intranasal administration of UC-MSCs secretome improved sensorimotor, animal’s gait, motor coordination and recognition memory impairments observed after neonatal hypoxic-ischemic brain injury at different stages of development. However, it was not possible to draw any conclusions about its impact on spatial memory and balance impairments. Moreover, the neonatal hypoxic-ischemic injury led to a brain lesion involving about 22% of the left hemisphere that was reduced to 10% with the secretome treatment. Despite its preliminary nature, the present work has shown that secretome administration positively impacted several functional parameters known to be affected by HIE, as well as in the recovery of the volume of injured tissue. Nonetheless, more studies need to be conducted to strengthen these conclusions. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-11-22 2023-10-09 2023-11-22T00:00:00Z 2026-10-06T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/masterThesis |
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masterThesis |
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http://hdl.handle.net/10400.6/13897 TID:203453999 |
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