title: Mesenchymal stem cells enhance α-synuclein clearance via M2 microglia polarization in experimental and human parkinsonian disorder.
abstract: Microglia in the brain show distinctive phenotypes that serve different functions. In particular, M2-polarized microglia are anti-inflammatory and phagocytic cells that serve a restorative function. In this study, we investigated whether mesenchymal stem cells (MSCs) enhance the phagocytic clearance of α-synuclein via M2 microglia polarization, and thereby exert neuroprotective effects in α-synuclein-enriched experimental models and patients with multiple system atrophy (MSA). Treatment of BV2 cells with α-synuclein induced an inflammatory phenotype, whereas co-culture of α-synuclein-treated BV2 cells with MSCs induced an anti-inflammatory M2 phenotype, with decreased α-synuclein levels and increased lysosomal activity, leading to greater viability of neuronal cells co-cultured with BV2 cells. Using IL-4 receptor siRNA in BV2 cells and IL-4 siRNA in MSCs, we found that M2 microglia polarization was induced by IL-4 secreted from MSCs. In α-synuclein-inoculated mice, MSC treatment induced M2 microglia polarization decreased α-synuclein levels, and had a prosurvival effect on neurons. Using IL-4 and IL-4 receptor knockout mice, we further confirmed that IL-4 secreted from MSCs induced phagocytic clearance of α-synuclein through M2 microglia polarization. Next, we found that the cerebrospinal fluid (CSF) from MSC-transplanted MSA patients induced microglia M2 polarization and had a prosurvival effect via enhanced clearance of α-synuclein in α-synuclein-treated BV2 cells. Finally, a serial CSF study demonstrated that changes in oligomeric α-synuclein from baseline to 1-year follow-up were greater in the CSF of MSC-transplanted MSA patients than in placebo-transplanted MSA patients. These findings indicate that MSCs exert a neuroprotective effect via the clearance of extracellular α-synuclein by controlling microglia M2 polarization, suggesting that MSCs could be used as a disease-modifying therapy for patients with α-synucleinopathies.
authors: Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea.|Severance Biomedical Science Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea.
authors: Hyun Jung
authors: HJ
authors: Park
authors: Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea.
authors: Se Hee
authors: SH
authors: Oh
authors: Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea.
authors: Ha Na
authors: HN
authors: Kim
authors: Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea.
authors: Yu Ju
authors: YJ
authors: Jung
authors: Department of Neurology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea. phisland@chol.net.|Severance Biomedical Science Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea. phisland@chol.net.
authors: Phil Hyu
authors: PH
authors: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D019578:Multiple System Atrophy / Q000601:surgery; D018696:Neuroprotective Agents / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D015847:Interleukin-4; D010751:Phosphopyruvate Hydratase
keywords: IL-4; M2-polarized microglia; Mesenchymal stem cells; α-Synuclein