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

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.