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Title: Bone Marrow Mesenchymal Stem Cells' Secretome Exerts Neuroprotective Effects in a Parkinson's Disease Rat Model
Authors: Mendes-Pinheiro, Bárbara
Anjo, Sandra I. 
Manadas, Bruno 
Da Silva, Jorge D.
Marote, Ana
Behie, Leo A.
Teixeira, Fábio G.
Salgado, António J. 
Keywords: Parkinson’s disease; mesenchymal stem cells; secretome; dopamine neurons; neuroprotection
Issue Date: 2019
Publisher: Frontiers Media S.A.
Project: This work was supported by Portuguese Foundation for Science and Technology: IF Development Grant (IF/00111/2013) to AS, Post-Doctoral Fellowship to FT (SFRH/BPD/118408/2016) and Doctoral Fellowship to BM-P (SFRH/BD/120124/2016); Canada Research Chair in Biomedical Engineering (LAB). 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 projects: POCI-01-0145-FEDER-029751; POCI-01-0145-FEDER-007038; POCI-01-0145-FEDER-032619; POCI-01-0145-FEDER-016428 (ref.: SAICTPAC/0010/2015), POCI-01-0145-FEDER-016795 (ref.: PTDC/NEU-SCC/7051/2014), POCI-01-0145-FEDER-029311 (ref.: PTDC/BTM-TEC/29311/2017), POCI-01-0145-FEDER-30943 (ref.: PTDC/MEC-PSQ/30943/2017) and PTDC/MED-NEU/27946/2017; UID/NEU/04539/2013 and POCI-01-0145-FEDER-007440. 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). Co-funded by the Programa Operacional Factores de Competitividade (QREN) and by The National Mass Spectrometry Network under the contract POCI-01-0145-FEDER-402-022125 (ref.: ROTEIRO/0028/2013). 
Serial title, monograph or event: Frontiers in Bioengineering and Biotechnology
Volume: 7
Abstract: Parkinson's disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the variety of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4, and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome led to the rescue of DA neurons, when compared to transplantation of hBMSCs themselves, which can explain the recovery of secretome-injected animals' behavioral performance in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete important exosome-related molecules, such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.
ISSN: 2296-4185
DOI: 10.3389/fbioe.2019.00294
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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