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Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer’s disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail...

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Autores principales: Yokokawa, Kazuki, Iwahara, Naotoshi, Hisahara, Shin, Emoto, Miho C., Saito, Taro, Suzuki, Hiromi, Manabe, Tatsuo, Matsumura, Akihiro, Matsushita, Takashi, Suzuki, Syuuichirou, Kawamata, Jun, Sato-Akaba, Hideo, Fujii, Hirotada G., Shimohama, Shun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918908/
https://www.ncbi.nlm.nih.gov/pubmed/31640102
http://dx.doi.org/10.3233/JAD-190817
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author Yokokawa, Kazuki
Iwahara, Naotoshi
Hisahara, Shin
Emoto, Miho C.
Saito, Taro
Suzuki, Hiromi
Manabe, Tatsuo
Matsumura, Akihiro
Matsushita, Takashi
Suzuki, Syuuichirou
Kawamata, Jun
Sato-Akaba, Hideo
Fujii, Hirotada G.
Shimohama, Shun
author_facet Yokokawa, Kazuki
Iwahara, Naotoshi
Hisahara, Shin
Emoto, Miho C.
Saito, Taro
Suzuki, Hiromi
Manabe, Tatsuo
Matsumura, Akihiro
Matsushita, Takashi
Suzuki, Syuuichirou
Kawamata, Jun
Sato-Akaba, Hideo
Fujii, Hirotada G.
Shimohama, Shun
author_sort Yokokawa, Kazuki
collection PubMed
description Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer’s disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice.
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spelling pubmed-69189082019-12-20 Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress Yokokawa, Kazuki Iwahara, Naotoshi Hisahara, Shin Emoto, Miho C. Saito, Taro Suzuki, Hiromi Manabe, Tatsuo Matsumura, Akihiro Matsushita, Takashi Suzuki, Syuuichirou Kawamata, Jun Sato-Akaba, Hideo Fujii, Hirotada G. Shimohama, Shun J Alzheimers Dis Research Article Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer’s disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice. IOS Press 2019-11-26 /pmc/articles/PMC6918908/ /pubmed/31640102 http://dx.doi.org/10.3233/JAD-190817 Text en © 2019 – IOS Press and the authors. All rights reserved https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Yokokawa, Kazuki
Iwahara, Naotoshi
Hisahara, Shin
Emoto, Miho C.
Saito, Taro
Suzuki, Hiromi
Manabe, Tatsuo
Matsumura, Akihiro
Matsushita, Takashi
Suzuki, Syuuichirou
Kawamata, Jun
Sato-Akaba, Hideo
Fujii, Hirotada G.
Shimohama, Shun
Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress
title Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress
title_full Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress
title_fullStr Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress
title_full_unstemmed Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress
title_short Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress
title_sort transplantation of mesenchymal stem cells improves amyloid-β pathology by modifying microglial function and suppressing oxidative stress
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918908/
https://www.ncbi.nlm.nih.gov/pubmed/31640102
http://dx.doi.org/10.3233/JAD-190817
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