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Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models.

ABSTRACT: Mesenchymal stem cells (MSCs) have emerged as a potential therapy for a range of neural insults. In animal models of multiple sclerosis, an autoimmune disease that targets oligodendrocytes and myelin, treatment with human MSCs results in functional improvement that reflects both modulation of the immune response and myelin repair. Here we demonstrate that conditioned medium from human MSCs (MSC-CM) reduces functional deficits in mouse MOG35–55-induced experimental autoimmune encephalomyelitis (EAE) and promotes the development of oligodendrocytes and neurons. Functional assays identified hepatocyte growth factor (HGF) and its primary receptor cMet as critical in MSC-stimulated recovery in EAE, neural cell development and remyelination. Active MSC-CM contained HGF, and exogenously supplied HGF promoted recovery in EAE, whereas cMet and antibodies to HGF blocked the functional recovery mediated by HGF and MSC-CM. Systemic treatment with HGF markedly accelerated remyelination in lysolecithin-induced rat dorsal spinal cord lesions and in slice cultures. Together these data strongly implicate HGF in mediating MSC-stimulated functional recovery in animal models of multiple sclerosis.

SUBMITTER: Bai L

PROVIDER: S-EPMC3427471 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models.

Bai Lianhua L Lennon Donald P DP Caplan Arnold I AI DeChant Anne A Hecker Jordan J Kranso Janet J Zaremba Anita A Miller Robert H RH

Nature neuroscience 20120601 6

Mesenchymal stem cells (MSCs) have emerged as a potential therapy for a range of neural insults. In animal models of multiple sclerosis, an autoimmune disease that targets oligodendrocytes and myelin, treatment with human MSCs results in functional improvement that reflects both modulation of the immune response and myelin repair. Here we demonstrate that conditioned medium from human MSCs (MSC-CM) reduces functional deficits in mouse MOG35–55-induced experimental autoimmune encephalomyelitis (E ...[more]

PMID: 22610068

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Project description:INTRODUCTION:Mesenchymal stem cells (MSCs) exert immunomodulatory functions by inducing the development and differentiation of naive T cells into T cells with an anti-inflammatory regulatory T cell (Treg) phenotype. Our previous study showed that hepatocyte growth factor (HGF) secreted by MSCs had immunomodulatory effects in the context of lipopolysaccharide (LPS) stimulation. We hypothesized that HGF is a key factor in the MSC-mediated regulation of the T helper 17 (Th17) cell/regulatory T (Treg) cell balance. METHODS:We investigated the effects of MSCs on the differentiation of CD4+ T cells and the functions of Th17/Treg cells in response to LPS stimulation by performing in vitro coculture experiments. MSCs were added to the upper chambers of cell culture inserts, and CD4+ T cells were plated in the lower chambers, followed by treatment with LPS or an anti-HGF antibody. Th17 (CD4+CD3+RORrt+) and Treg (CD4+CD25+Foxp3+) cell frequencies were analysed by flow cytometry, and the expression of Th17 cell- and Treg cell-related cytokines in the CD4+ T cells or culture medium was measured by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Neutrophil functions were determined by flow cytometry after a coculture with Th17/Treg cells. RESULTS:The percentage of CD4+CD25+Foxp3+ cells was significantly increased in the CD4+ T cell population, while the percentage of CD4+CD3+RORrt+ cells was significantly decreased after MSC coculture. However, the MSC-induced effect was significantly inhibited by the anti-HGF antibody (p?<?0.05). Furthermore, MSCs significantly inhibited the CD4+ T cell expression of IL-17 and IL-6 but increased the expression of IL-10 (p?<?0.05 or p?<?0.01); these effects were inhibited by the anti-HGF antibody (p?<?0.05). In addition, CD4+ T cells cocultured with MSCs significantly inhibited neutrophil phagocytic and oxidative burst activities (p?<?0.05 or p?<?0.01); however, these MSC-induced effects were inhibited by the anti-HGF antibody (p?<?0.05). CONCLUSION:These data suggested that MSCs induced the conversion of fully differentiated Th17 cells into functional Treg cells and thereby modulated the Th17/Treg cell balance in the CD4+ T cell population, which was partly attributed to HGF secreted by the MSCs.

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Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models.

Publications

Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models.

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