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MMP2: The Key to MSC-based Treatments of PD?

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Review of “The Cleavage Effect of Mesenchymal Stem Cell and Its Derived Matrix Metalloproteinase-2 on Extracellular α-Synuclein Aggregates in Parkinsonian Models” from Stem Cells Translational Medicine by Stuart P. Atkinson

The loss of dopaminergic neurons and the presence of aggregates of the -synuclein protein [1] represent two important characteristics of the devastating neurodegenerative disorder Parkinson’s Disease (PD). In terms of PD treatment strategies, studies from the laboratory of Phil Hyu Lee (Yonsei University College of Medicine, Seoul, Republic of Korea) have reported that mesenchymal stem cells (MSCs) exhibit potent neuroprotective effects in animal models of PD. 

Now, they return with a new Stem Cells Translational Medicine study in which the team assess the role of MSCs and MSC-secreted factors in the degradation of -synuclein aggregates and highlight a key role for the matrix metalloproteinase-2 MMP-2 [2].

Initial cell-free studies demonstrated that the addition of conditioned medium from MSCs (MSC-CM) promoted the disassembly of preformed a-synuclein aggregates in solution and a reduction in the levels of insoluble and oligomeric forms of α-synuclein. The addition of α-synuclein aggregates to SH-SY5Y neuroblastoma cells in vitro led to a reduction in cellular viability; however, MSC-CM addition negated this loss and preserved neuronal viability. 

Subsequent proteomic analyses and cell-based confirmatory assays identified MMP-2 as one MSC-derived factor with α-synuclein fibrils degrading abilities. Encouragingly, the study also discovered that MSCs or MSC-CM injection into the brains of a mouse model of PD reduced the levels of extracellular α-synuclein oligomers in the midbrain concomitant with a reduction in apoptotic cell death signaling.

These exciting findings suggest that MSCs or MSC-secreted factors (the “secretome”) could form part of an effective strategy to treat diseases/disorders such as PD by targeting the degradation of α-synuclein aggregates. Indeed, a previously featured study here at the Stem Cells Portal demonstrated that the bioreactor-potentiated hMSC secretome contained important neuroregulatory factors that attenuated PD-related deficits in animal behavior, motor performance, and motor coordination and promoted the survival of dopaminergic neurons [3]. 

Are MSCs the way forward for the treatment of neurodegenerative diseases such as PD? Stay tuned to the Stem Cells Portal to find out!

References

  1. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature 1997;388:839-840.
  2. Oh SH, Kim HN, Park HJ, et al. The Cleavage Effect of Mesenchymal Stem Cell and Its Derived Matrix Metalloproteinase-2 on Extracellular alpha-Synuclein Aggregates in Parkinsonian Models. Stem Cells Transl Med 2016;
  3. Teixeira FG, Carvalho MM, Panchalingam KM, et al. Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal Behavior in a Rat Model of Parkinson's Disease. STEM CELLS Translational Medicine 2017;6:634-646.