title: Mesenchymal Stem Cells Modulate the Functional Properties of Microglia via TGF-β Secretion.
abstract: : The regulation of microglial cell phenotype is a potential therapeutic intervention in neurodegenerative disease. Previously, we reported that transforming growth factor-β (TGF-β) levels in mesenchymal stromal cells (MSCs) could be used as potential biological markers to predict the effectiveness of autologous MSC therapy in patients with amyotrophic lateral sclerosis. However, the underlying mechanism of TGF-β in MSCs was not fully elucidated in determining the functional properties of microglia. In this study, we aimed to clarify the role of TGF-β that is involved in MSC effectiveness, especially focusing on microglia functional properties that play a pivotal role in neuroinflammation. We found that MSC-conditioned media (MSC-CM) inhibited proinflammatory cytokine expression, restored alternative activated microglia phenotype markers (fractalkine receptor, mannose receptor, CD200 receptor), and enhanced phagocytosis in lipopolysaccharide (LPS)-stimulated microglia. In addition, TGF-β in MSC-CM played a major role in these effects by inhibiting the nuclear factor-κB pathway and restoring the TGF-β pathway in LPS-stimulated microglia. Recombinant TGF-β also induced similar effects to MSC-CM in LPS-stimulated microglia. Therefore, we propose that MSCs can modulate the functional properties of microglia via TGF-β secretion, switching them from a classically activated phenotype to an inflammation-resolving phenotype. The latter role may be associated with the inhibition of neuroinflammatory processes in neurodegenerative disorders.
  
  
  CONCLUSIONS
  The results of this study showed that microglia functional properties may be modulated depending on the composition and quantity of mesenchymal stromal cell (MSC)-secreting factors. Transforming growth factor (TGF)-β is proposed as a modulator of microglia functional properties among MSC-secreting factors, and this study aligns with a previous clinical study by these same authors. TGF-β releasing capacity could be an important factor enhancing the therapeutic efficacy of MSCs in clinical trials.
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Noh
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Su Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Ki-Wook
authors.initials: KW
authors.lastname: Oh
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.|Department of Neural Development and Disease and Behavioral Neuroepigenetics Laboratory, Korea Brain Research Institute, Daegu, Republic of Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Cho
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Jinseok
authors.initials: J
authors.lastname: Park
authors.affiliation: Bioengineering Institute, CORESTEM Inc., Seoul, Republic of Korea.
authors.forename: Kyung-Suk
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, CHA University, Gyeonggi-do, Republic of Korea minsoo100@cha.ac.kr kimsh1@hanyang.ac.kr.
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kwon
authors.affiliation: Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea minsoo100@cha.ac.kr kimsh1@hanyang.ac.kr.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
keywords: Mesenchymal stem cells; Microglia; Neurodegenerative diseases; TGF-β