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 MOG-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
Studies have shown modulation of the immune response that stops myelin damage and the evidence for real myelin repair is mariginal. Likewise the immune modulatory effect of mesenchymal cells has been modest. In this study human mesenchymal stem cells were grown in cell culture. They took the growth medium in which they were grown, this is the conditioned-medium that would contain the things that these cells secrete. The authors of this study then injected the conditioned medium into mice with an MS-like disease and the immune inhibitory effect was very marked. They reported that the inhibitory factor in the conditioned medium was hepatocyte growth factor. This works by targeting the hepatoctye growth factor. receptor called cMet.
They showed that when they extracted the CNS from treated animals they had less cytokines except the Th2 cytokines, so mechanism sorted, but there were less cells in the CNS because the HGF was immunosuppressive so you would expect less cytokines and less myelin and axon damage, which is exactly what they found as this would occur with any immunosuppressive. There was limited evidence of remyelination. However, if you have a potent immunosuppressive activity that turns the active disease off, it would be expected that any demyelination that is present would repair itself, compared to no treatment where the disease an axon and myelin loss continues. So this is abit of a Shania, as there is no compelling evidence of repair that cannot be attributed to immunosuppression.
They could block the effect of HGF by blockade of the receptor for HGF so there are new targets for immunosuppression. They do not think that HGF hangs around very long and so they are not
sure how it could have a long term effect. It is clear that HGF is
immunosuppressive and EAE in C57BL/6 is a one-hit neurodegenerative
attack so there is the reason…….simples, but this gives me ideas and we have way to make this hang
around for longer.
There was however some evidence that when HGF stimulated neural stem cells mobilization to become nerves and oligodendrocytes and more importantly they looked at a chemical induced demyelination model and found that HGF treatment resulted in less myelin loss and appearred to promote repair and remyelination. This effect was also noted in demyelination cell cultures and so looks promising. Therefore, through investigating stem cell function, new targets for repair and immunomodulation are being found, which must be said, seem to work better than similar experiments with the stem cells themselves.
This is a new target, mesenchymal stem cell trials are occuring.