The Cleavage Effect of Mesenchymal Stem Cell and Its Derived Matrix Metalloproteinase-2 on Extracellular α-Synuclein Aggregates in Parkinsonian Models

Abstract

Ample evidence has suggested that extracellular α‐synuclein aggregates would play key roles in the pathogenesis and progression of Parkinsonian disorders (PDs). In the present study, we investigated whether mesenchymal stem cells (MSCs) and their derived soluble factors could exert neuroprotective effects via proteolysis of extracellular α‐synuclein. When preformed α‐synuclein aggregates were incubated with MSC‐conditioned medium, α‐synuclein aggregates were disassembled, and insoluble and oligomeric forms of α‐synuclein were markedly decreased, thus leading to a significant increase in neuronal viability. In an animal study, MSC or MSC‐conditioned medium treatment decreased the expression of α‐synuclein oligomers and the induction of pathogenic α‐synuclein with an attenuation of apoptotic cell death signaling. Furthermore, we identified that matrix metalloproteinase‐2 (MMP‐2), a soluble factor derived from MSCs, played an important role in the degradation of extracellular α‐synuclein. Our data demonstrated that MSCs and their derived MMP‐2 exert neuroprotective properties through proteolysis of aggregated α‐synuclein in PD‐related microenvironments. Stem Cells Translational Medicine 2017;6:949–961

Alpha-synuclein fragments trigger distinct aggregation pathways

“…Several extracellular proteases are known to cleave αSyn, e.g. plasmin 32 , neurosin 33,34 and several metalloproteinases [35][36][37][38] . Although we were not able to identify the active protease (s) in our experimental system, a comparison between our MS data and previously published cleavage sites of αSyn suggests that plasmin and matrix metalloproteases 3 and 9 could be suitable candidates 32,36 .…”

Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy

“…It is well established that MSCs can migrate to injury sites and secrete various neurotrophic factors that exert neuroprotective effects [15,24], via anti-apoptotic [25], supportive (i.e., stimulation of mitosis, proliferation, and differentiation) [26], and angiogenic effects [25]. In our previous experimental studies, we have demonstrated the therapeutic potential of MSCs in animal models of parkinsonian disorders through antiin ammatory action [27], autophagy modulation [28], stabilization of axonal transport [18], control of microglia M2 polarization [29], proteolysis of α-synuclein aggregates [17], and inhibition of α-synuclein transmission [16], which might modulate α-synuclein-related microenvironments. Furthermore, in two previous clinical trials [12,13], we demonstrated the safety and clinical e cacy of intra-arterial and intravenous administration of autologous BM-MSCs in patients with MSA-C.…”

“…Only the administration of autologous mesenchymal stem cells (MSCs) via the intra-arterial/intravenous [12,13] or intrathecal routes [14] have shown any effect. Indeed, MSCs secrete various cytokines and growth factors that exert neuroprotective effects [15] and directly modulate α-synuclein-related neurodegeneration [16][17][18][19]. As such, MSCs may be the most suitable candidate for MSA treatment.…”

Cell secretome based approaches in Parkinson’s disease regenerative medicine

“…Based on the proteomic analysis of the secretome, we found that BM-MSCs secreted not only important neurotrophic factors, such as vascular endothelial growth factor (VEGF), BDNF, interleukin-6 (IL-6) and GDNF, but also other potential neuroregulatory molecules, namely cystatin C (Cys C), glia-derived nexin, galectin-1, and PEDF [38]. Recently, it was also demonstrated the ability of MSCs secretome to degrade extracellular α-synuclein both in vitro and in vivo, an effect partially mediated by matrix metalloproteinase-2 (MMP-2) [39].…”