Mesenchymal Stem Cells Modulate the Functional Properties of Microglia via TGF‐β Secretion

• Published in: Stem cells translational medicine 2016-11, Vol.5 (11), p.1538-1549
• Main Authors: Noh, Min Young, Lim, Su Min, Oh, Ki-Wook, Cho, Kyung-Ah, Park, Jinseok, Kim, Kyung-Suk, Lee, Su-Jung, Kwon, Min-Soo, Kim, Seung Hyun
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Clinical trials; Cytokines; Data analysis; Disease; Enabling Technologies for Cell-Based Clinical Translation; Genotype & phenotype; Growth factors; Homeostasis; Inflammation; Laboratory animals; Lipopolysaccharides; Mesenchymal stem cells; Mesenchyme; Microglia; Multiple sclerosis; Neurodegenerative diseases; Phagocytosis; Phenotypes; R&D; Research & development; Studies; TGF-β; Transforming growth factor; Transforming growth factor-b; Tumor necrosis factor-TNF
• ISSN: 2157-6564; 2157-6580
• DOI: 10.5966/sctm.2015-0217

Mesenchymal stromal cell‐conditioned media (MSC‐CM) inhibited proinflammatory cytokine expression, restored alternative activated microglia phenotype markers, and enhanced phagocytosis in lipopolysaccharide (LPS)‐stimulated microglia. Transforming growth factor‐β (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 effects similar to those of MSC‐CM in LPS‐stimulated microglia. Acknowledgements 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. 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