Abstract
Background: 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 wide array 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. Methods: 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. Findings: This work demonstrates that the injection of hBMSCs secretome potentiated the histological recovery of DA neurons, when compared to transplantation of hBMSCs themselves, a fact that probably explains the improved behavioral performance of secretome-injected animals 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 a variety of important exosome-related molecules such as those related with the ubiquitin-proteasome and histone systems. Interpretation: 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. Funding Statement: This work was supported by Portuguese Foundation for Science and Technology: IF Development Grant (IF/00111/2013) to AJS, Post-Doctoral Fellowship to F.G. Teixeira (SFRH/BPD/118408/2016) and Doctoral Fellowship to B. Mendes-Pinheiro (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; POCI01-0145-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 POCI01-0145-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). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Cells were isolated in respect with the protocols and strict ethical guidelines previously established and approved by the Conjoint Health Research Ethics Board (CHREB, University of Calgary, Canada; ID: E18786). Eight-weeks old Wistar-Han male rats were used according to the Portuguese national authority for animal research, Direcao Geral de Alimentacao e Veterinaria (ID: DGAV28421) and Ethical Subcommittee in Life and Health Sciences (SECVS; ID: SECVS-008/2013, University of Minho).
Highlights
Parkinson’s disease (PD) represents the second most common neurodegenerative disorder after Alzheimer’s disease, affecting ∼1% of the population worldwide over 65 years old (Vos et al, 2017)
The main goal of this study was to determine the impact of the injection of the secretome-derived from hBMSCs as a potential therapy for PD, when compared to what is considered the current gold standard in the field of cell-based therapies for regenerative medicine, that is the stem cell-based transplantation approaches
When the forelimb reaching and grasping abilities were assessed using the staircase test, we observed that the injection of hBMSCs secretome improved the success rate of eaten pellets of the treated animals when compared to the untreated group 6-OHDA (Figure 4B)
Summary
Parkinson’s disease (PD) represents the second most common neurodegenerative disorder after Alzheimer’s disease, affecting ∼1% of the population worldwide over 65 years old (Vos et al, 2017). Its pathogenesis is characterized by the death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc), leading to a decrease of DA levels in the striatum, which causes typical motor dysfunctions, such as tremor ate rest, rigidity, bradykinesia, among others (Przedborski, 2017; Axelsen and Woldbye, 2018). Another important hallmark feature of PD is the presence of Lewy bodies that are abnormal aggregates of proteins enriched in α-synuclein (Axelsen and Woldbye, 2018). The use of the secretome derivatives could bypass potential issues associated with cell transplantation including the number of available cells for transplantation and its survival after this procedure, immune compatibility, tumorigenicity, and infection transmission (Tran and Damaser, 2015)
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