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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.

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Figure 1: Conditioned growth medium from human MSCs biases the development of neurosphere derived cells toward oligodendrocytes and neurons, and promotes functional recovery in MOG35–55-induced EAE.
Figure 2: The activity of MSC-CM to enhance functional recovery in EAE is dependent on a 1–100-kDa fraction.
Figure 3: Human MSC-CM100kDa contains HGF and HGF promotes functional and histological recovery in EAE.
Figure 4: Inhibition of HGF signaling with cMet antibodies negates the capacity of both HGF and MSC-CM to induce functional recovery and reverses EAE-induced changes in cytokine expression.
Figure 5: Inhibition of HGF signaling with cMet or anti-HGF blocks the ability of MSC-CM100kDa and HGF to alter the development and migration of neural cells from neurospheres.
Figure 6: Systemic HGF treatment stimulates remyelination of rat spinal cord LPC lesions.

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Acknowledgements

We thank M. Hitomi for electron microscopy support, D. Carrino for help with fractionation, S. Miller for microfluidics and A. Kerstetter for help with cell culture. This study was supported by the Myelin Repair Foundation and US National Institutes of Health grant NS 30800 (R.H.M.) and the Virginia and David Baldwin Fund (A.I.C., D.P.L.).

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L.B., A.I.C. and R.H.M. conceived the study and experimental design. D.P.L. and A.I.C. prepared and processed the mesenchymal stem cells. L.B. performed all EAE experiments, immunohistochemistry and data analysis. A.Z. designed and conducted the slice and culture studies. J.H. and J.K. conducted the LPC lesion studies. L.B., A.I.C., A.D. and R.H.M. wrote the paper and designed the figures. All authors discussed the results and implications and commented on the manuscript at all stages.

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Correspondence to Robert H Miller.

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Bai, L., Lennon, D., Caplan, A. et al. Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models. Nat Neurosci 15, 862–870 (2012). https://doi.org/10.1038/nn.3109

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