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Insights into the Effects of Mesenchymal Stem Cell-Derived Secretome in Parkinson's Disease.

ABSTRACT: Mesenchymal stem cell (MSC)-derived secretome demonstrated therapeutic effects like those reported after MSCs transplantation. MSC-derived secretome may avoid various side effects of MSC-based therapy, comprising undesirable differentiation of engrafted MSCs and potential activation of the allogeneic immune response. MSC-derived secretome comprises soluble factors and encapsulated extravesicles (EVs). MSC-derived EVs comprise microvesicles, apoptotic bodies, and exosomes. In this review, we focus on the recent insights into the effects of MSC-derived secretome in Parkinson's disease (PD). In particular, MSC-derived secretome and exosomal components counteracted neuroinflammation and enhanced antioxidant capacity and neurotrophic factors expression. In light of the insights reported in this review, MSC-derived secretome or their released exosomes may be used as a potential therapeutic approach or as adjuvant therapy to counteract the disease progression and improve PD symptoms. Also, MSC-derived secretome may be used as a vehicle in cell transplantation approaches to enhance the viability and survival of engrafted cells. Furthermore, since exosomes can cross the blood-brain barrier, they may be used as biomarkers of neural dysfunction. Further studies are necessary to fully characterize the bioactive molecules present in the secretome and to create a new, effective, cell-free therapeutic approach towards a robust clinical outcome for PD patients.

SUBMITTER: d'Angelo M

PROVIDER: S-EPMC7432166 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Insights into the Effects of Mesenchymal Stem Cell-Derived Secretome in Parkinson's Disease.

d'Angelo Michele M Cimini Annamaria A Castelli Vanessa V

International journal of molecular sciences 20200723 15

Mesenchymal stem cell (MSC)-derived secretome demonstrated therapeutic effects like those reported after MSCs transplantation. MSC-derived secretome may avoid various side effects of MSC-based therapy, comprising undesirable differentiation of engrafted MSCs and potential activation of the allogeneic immune response. MSC-derived secretome comprises soluble factors and encapsulated extravesicles (EVs). MSC-derived EVs comprise microvesicles, apoptotic bodies, and exosomes. In this review, we focu ...[more]

PMID: 32718092

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Project description: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.

Project description:BackgroundNeuroinflammation plays a key role in PD pathogenesis, and allogeneic bone marrow-derived mesenchymal stem cells can be used as an immunomodulatory therapy.ObjectiveThe objective of this study was to prove the safety and tolerability of intravenous allogeneic bone marrow-derived mesenchymal stem cells in PD patients.MethodsThis was a 12-month single-center open-label dose-escalation phase 1 study of 20 subjects with mild/moderate PD assigned to a single intravenous infusion of 1 of 4 doses: 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg, evaluated 3, 12, 24, and 52 weeks postinfusion. Primary outcome safety measures included transfusion reaction, study-related adverse events, and immunogenic responses. Secondary outcomes included impact on peripheral markers, PD progression, and changes in brain perfusion.ResultsThere were no serious adverse reactions related to the infusion and no responses to donor-specific human leukocyte antigens. Most common treatment-emergent adverse events were dyskinesias (20%, n = 4) with 1 emergent and 3 exacerbations; and hypertension (20%, n = 4) with 3 transient episodes and 1 requiring medical intervention. One possibly related serious adverse event occurred in a patient with a 4-year history of lymphocytosis who developed asymptomatic chronic lymphocytic leukemia. Peripheral inflammation markers appear to be reduced at 52 weeks in the highest dose including, tumor necrosis factor-α (P < 0.05), chemokine (C-C motif) ligand 22 (P < 0.05), whereas brain-derived neurotrophic factor (P < 0.05) increased. The highest dose seems to have demonstrated the most significant effect at 52 weeks, reducing the OFF state UPDRS motor, -14.4 (P < 0.01), and total, -20.8 (P < 0.05), scores.ConclusionA single intravenous infusion of allogeneic bone marrow-derived mesenchymal stem cells at doses of 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg is safe, well tolerated, and not immunogenic in mild/moderate PD patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Insights into the Effects of Mesenchymal Stem Cell-Derived Secretome in Parkinson's Disease.

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Insights into the Effects of Mesenchymal Stem Cell-Derived Secretome in Parkinson's Disease.

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