Bárbara Filipa Mendes Pinheiro - ICVS, University of Minho
Title: A New Paradigm for Parkinson’s Disease Regenerative Medicine based on the Secretome of Mesenchymal Stem Cells
Abstract:
Parkinson’s disease (PD) is a progressive movement disorder that results from the death of dopaminergic neurons, mainly in the nigrostriatal pathway, leading to the appearance of characteristic motor symptoms. Current PD treatments are focused on reducing the symptoms: none 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) 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 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 work we aimed to: 1) Characterize the secretome of hMSCs through proteomic-based approaches; 2) Determine the role of hMSCs secretome as a modulator of neuronal differentiation and 3) Investigate the effects of the hMSCs secretome in a rat model of PD, in comparison with cell transplantation. In vitro experiments revealed that MSCs secretome was able to differentiate human neural progenitor cells (hNPCs) towards a neuronal phenotype (MAP-2+ and DCX+ positive cells). Additionally, it was also possible to observe that the injection of the hMSCs secretome in a 6- hydroxydopamine (6-OHDA)-rat model of PD potentiated the recovery of dopaminergic neurons (estimated by neuronal densities in substantia nigra and striatum) when compared to the untreated group 6-OHDA, and those transplanted with cells. Similar outcomes were observed in the motor performance of these animals as assessed by the rotarod and staircase tests. Finally, proteomic characterization of hMSCs 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. In addition to these results, besides the dopaminergic survival, it has also been described that the modulation of neurogenesis may also play a role in the recovery of PD. Preliminary data of subependymal zone (SEZ) and striatum analysis indicates that hMSCs secretome seems to be more prone to induce dopaminergic neuronal differentiation in the lesion side.
Title: A New Paradigm for Parkinson’s Disease Regenerative Medicine based on the Secretome of Mesenchymal Stem Cells
Abstract:
Parkinson’s disease (PD) is a progressive movement disorder that results from the death of dopaminergic neurons, mainly in the nigrostriatal pathway, leading to the appearance of characteristic motor symptoms. Current PD treatments are focused on reducing the symptoms: none 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) 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 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 work we aimed to: 1) Characterize the secretome of hMSCs through proteomic-based approaches; 2) Determine the role of hMSCs secretome as a modulator of neuronal differentiation and 3) Investigate the effects of the hMSCs secretome in a rat model of PD, in comparison with cell transplantation. In vitro experiments revealed that MSCs secretome was able to differentiate human neural progenitor cells (hNPCs) towards a neuronal phenotype (MAP-2+ and DCX+ positive cells). Additionally, it was also possible to observe that the injection of the hMSCs secretome in a 6- hydroxydopamine (6-OHDA)-rat model of PD potentiated the recovery of dopaminergic neurons (estimated by neuronal densities in substantia nigra and striatum) when compared to the untreated group 6-OHDA, and those transplanted with cells. Similar outcomes were observed in the motor performance of these animals as assessed by the rotarod and staircase tests. Finally, proteomic characterization of hMSCs 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. In addition to these results, besides the dopaminergic survival, it has also been described that the modulation of neurogenesis may also play a role in the recovery of PD. Preliminary data of subependymal zone (SEZ) and striatum analysis indicates that hMSCs secretome seems to be more prone to induce dopaminergic neuronal differentiation in the lesion side.