Injections of conditioned medium or recombinant HGF mediate remyelination and immune suppression through c-Met signaling.

Scientists have identified a factor in the conditioned medium of mesenchymal stem cell (MSCs) cultures that appears to play a key role in the therapeutic effects of MSC-based therapy in multiple sclerosis (MS). Studies by Case Western Reserve University researchers in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS demonstrated that treatment using conditioned medium from cultured human MSCs (MSC-CM) was sufficient to reduce functional deficits, promote the development of new myelinating oligodendrocytes and neurons, as well as suppress the influx of immune cells and inflammatory cytokine release.

Subsequent functional assays identified hepatocyte growth factor (HGF) and its primary receptor cMet as critical for MSC-stimulated recovery in EAE, neural cell development, and remyelination. Reporting their findings in Nature Neuroscience, Robert H. Miller and colleagues suggest their results indicate the HGF-cMet pathway may provide new therapeutic opportunities for treating multiple sclerosis. Their published paper is titled “Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models.”

Multiple sclerosis is an autoimmune disease characterized by loss of myelin on nerve cells and the death of myelinating oligodendrocytes. In parallel with therapeutic approaches based on modulating the immune response, more recent work has focused on promising MSC-based cell therapies a an approach to promoting remyelination and functional recovery as well as suppressing further immunological attack.

The Case Western Team looked to see whether soluble factors released by MSCs were integral to the therapeutic effects of MSCs in the EAE model of MS. The researchers first demonstrated that injections of human MSC-CM led to marked functional improvements in EAE mice and identified HGF as the candidate molecule responsible for the therapeutic effects.

Animals then administered with recombinant HGF injections intravenousy for five days demonstrated notable functional improvements after 30 days, which was closely associated with histological improvements including markedly reduced numbers of demyelinated axons, increased thickness of myelin sheaths in areas of lesions, and lower levels of inflammatory cell infiltration. Promisingly, HGF injections were similarly capable of promoting remyelination in the spinal cords of LPC lesion experimental rats, which represent a model for nonimmune-mediated demyelination.

These functional benefits of HGF therapy were found to be mediated through the tyrosine receptor kinase cMet, which is the most well-characterized receptor for HGF, the authors note. Mice treated with a cMet antibody failed to respond to therapy with HGF or MSC-CM and showed no evidence of immune suppression. c-Met signaling was also critical to the effects of HGF on oligodendrocyte precursor cell development in vitro and for promoting oligodendrocyte migration to areas of demyelination in EAE-derived neurospheres.

A function for HGF in MS hasn’t yet been identified, the team admits. Indeed, while previous research had found raised levels of HGF in the cerebrospinal fluid of patients with MS and other neurological diseases, it had been proposed that this elevation was linked with disease pathology.

“Our studies suggest it is more likely a reflection of an endogenous repair process stimulated by the disease,” the Case Western researchers point out. “Indeed, it may be that susceptibility or disease progression in multiple sclerosis is, in part, a reflection of the capacity of endogenous MSCs to release HGF. These studies raise the possibility that the HGF-cMet pathway may provide new therapeutic opportunities for the treatment of multiple sclerosis.”

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