Publicação
Mesenchymal stem cells secretome in Parkinson’s disease regenerative medicine
| Resumo: | Parkinson’s disease (PD) represents the second most common neurodegenerative brain disorder, which is clinically characterized by the progressive degeneration of dopaminergic neurons (DAergic neurons), mainly in the nigrostriatal pathway, leading to the appearance of characteristic motor and non-motor symptoms. Currently, pharmacological and surgical treatments are the most common approaches for the treatment of PD. However, so far, all of these treatments are focused on reducing the symptoms. In fact, they do not slow down or reverse the degenerative process, imposing the need for innovative therapeutical approaches. The use of adult stem cells cell-based strategy has emerged as a potential alternative therapy for PD, in which, among a number of promising stem cell sources, human mesenchymal stem cells (hMSCs) and neural progenitors cells (hNPCs) have stand out as a valid therapeutic option. Indeed, over the last years, a substantial effort has been performed in order to address the impact of hMSCs and hNPCs in central nervous system repair. Recently, and from an application point of view, several studies have claimed that the therapeutical effects of stem cells is mainly mediated by their trophic action namely, through their capacity of secreting a wide panel of neuroregulatory molecules (e.g. neurotrophic factors, cytokines, vesicles), which is defined as secretome. Thus, based in all these concepts, in this thesis we aimed to: 1) Characterize the secretome of hMSCs and hNPCs through proteomic-based approaches; 2) Determine the role of hMSCs and hNPCs secretome as a modulator of neuronal differentiation and 3) Investigate the effects of the hMSCs and hNPCs secretome in a rat model of PD, in comparison with cell transplantation. In vitro, experiments revealed that the secretome of hMSCs induced a more robust neuronal differentiation when compared to the one obtained from hNPCs. Additionally, it was also possible to observe that the injection of the secretome of both hMSCs and hNPCs in a 6-hydroxydopamine (6-OHDA)-rat model of PD potentiated the recovery of DAergic neurons (estimated by neuronal densities in substantia nigra and striatum) when compared to the untreated group 6-OHDA, and those transplanted with cells (hMSCs and hNPCs). Similar outcomes were observed in the motor performance of these animals as assessed by the rotarod and staircase tests. Finally, proteomic characterization of hMSCs and hNPCs secretome revealed that these cells were able to secrete important molecules with neuroregulatory actions such as, Galectin-1, 14-3-3 proteins, PEDF, DJ-1, whereby may support the effects observed both in vitro and in vivo. Overall, we concluded that the use of secretome per se was able to partially revert the motor phenotype and the neuronal structure of PD animals, indicating that the secretome of stem cells could represent a novel therapeutic tool for the treatment of PD. |
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| Autores principais: | Pinheiro, Bárbara Filipa Mendes |
| Assunto: | Ciências Médicas |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Parkinson’s disease (PD) represents the second most common neurodegenerative brain disorder, which is clinically characterized by the progressive degeneration of dopaminergic neurons (DAergic neurons), mainly in the nigrostriatal pathway, leading to the appearance of characteristic motor and non-motor symptoms. Currently, pharmacological and surgical treatments are the most common approaches for the treatment of PD. However, so far, all of these treatments are focused on reducing the symptoms. In fact, they do not slow down or reverse the degenerative process, imposing the need for innovative therapeutical approaches. The use of adult stem cells cell-based strategy has emerged as a potential alternative therapy for PD, in which, among a number of promising stem cell sources, human mesenchymal stem cells (hMSCs) and neural progenitors cells (hNPCs) have stand out as a valid therapeutic option. Indeed, over the last years, a substantial effort has been performed in order to address the impact of hMSCs and hNPCs in central nervous system repair. Recently, and from an application point of view, several studies have claimed that the therapeutical effects of stem cells is mainly mediated by their trophic action namely, through their capacity of secreting a wide panel of neuroregulatory molecules (e.g. neurotrophic factors, cytokines, vesicles), which is defined as secretome. Thus, based in all these concepts, in this thesis we aimed to: 1) Characterize the secretome of hMSCs and hNPCs through proteomic-based approaches; 2) Determine the role of hMSCs and hNPCs secretome as a modulator of neuronal differentiation and 3) Investigate the effects of the hMSCs and hNPCs secretome in a rat model of PD, in comparison with cell transplantation. In vitro, experiments revealed that the secretome of hMSCs induced a more robust neuronal differentiation when compared to the one obtained from hNPCs. Additionally, it was also possible to observe that the injection of the secretome of both hMSCs and hNPCs in a 6-hydroxydopamine (6-OHDA)-rat model of PD potentiated the recovery of DAergic neurons (estimated by neuronal densities in substantia nigra and striatum) when compared to the untreated group 6-OHDA, and those transplanted with cells (hMSCs and hNPCs). Similar outcomes were observed in the motor performance of these animals as assessed by the rotarod and staircase tests. Finally, proteomic characterization of hMSCs and hNPCs secretome revealed that these cells were able to secrete important molecules with neuroregulatory actions such as, Galectin-1, 14-3-3 proteins, PEDF, DJ-1, whereby may support the effects observed both in vitro and in vivo. Overall, we concluded that the use of secretome per se was able to partially revert the motor phenotype and the neuronal structure of PD animals, indicating that the secretome of stem cells could represent a novel therapeutic tool for the treatment of PD. |
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