Which research results in mice will help humans with MS? Now there’s a way to tell – UB News Center

By daniellenierenberg

BUFFALO, N.Y. People with multiple sclerosis (MS) knowall too well the frustration of hearing that success in treatingthe disease in mice had little or no effect in humans.

Unfortunately, with no large animal models for MS, results thatsuggest promising new treatments in mice often are ineffective inhumans.

Now, University at Buffalo researchers have developed andsuccessfully tested a method for determining how relevant to thehuman disease findings are from mouse models. The researchwas published Aug. 8 in Stem Cell Reports.

This is an important resource for the field as it allowsus to compare human and rodent cells, and provides a point ofreference to understand whether or not gene expression patterns areconserved between species, said Fraser Sim, PhD, seniorauthor and associate professor in the Department of Pharmacologyand Toxicology in the Jacobs School of Medicine and BiomedicalSciences at UB. Co-first authors are Suyog U. Pol PhD, now apostdoctoral fellow, and Jessie J. Polanco, a doctoral candidate,both in the medical school.

MS trial failures

There have been so many failures in clinical trials forMS when promising observations are translated from small animalmodels to the clinic, Sim said. Our primarymotivation was to try to understand, at a molecular level, how thehuman cells responsible for synthesizing myelin differ from theirmuch-better-studied mouse counterparts.

MS and some other neurological diseases occur when there isdamage to myelin the fatty sheath that allows nerve cellsto communicate. So the myelin-producing cells, called humanoligodendrocyte progenitor cells, or OPCs, found in the brain andspinal cord have been a major focus of efforts to better understandMS and develop potential new treatments for it.

Sim explained that undifferentiated OPCs are frequently found inthe brain lesions of MS patients, so boosting the differentiationof these cells could lead to myelination and a reduction ofsymptoms.

From OPCs to oligodendrocytes

One reason why so many clinical trials fail may be because offundamental differences in the types and levels of genes expressedbetween mice and humans. Sim and his colleagues addressed thisquestion by performing gene-expression analysis on differentiatinghuman OPCs.

In this paper, we describe the transcriptional eventsthat underlie how human OPCs develop into oligodendrocytes,said Sim.

To do it, they used a network analysis software tool calledweighted gene coexpression network analysis (WCGNA). The softwareclusters together genes with similar patterns of expression. Italso allows for analysis of both conserved and divergent geneexpression between humans and rodents.

WCGNA looks at the relationships between genes ratherthan absolute differences between conditions in any givenexperiment, Sim said.

He added that the information encoded in levels of geneexpression increasing or decreasing is very reliable andreproducible.

We performed WCGNA in exactly the same manner on cellsisolated from mice, rats and humans, and prepared these cells in asclose to matched conditions as possible, trying to keep things assimilar as possible to facilitate this comparison, saidSim.

It turned out several of the genes the team had identified asrelevant to human disease also are involved in mouse developmentand mouse models of myelin disease.

New myelin-repairing gene

Based on its findings from that analysis, the team had predictedthat GNB4, a protein involved in signal transduction, would beinvolved in the development of OPCs in humans. The researchersfound that over-production of GNB4, a protein involved in thetransduction of extracellular signals, could cause human OPCs torapidly undergo myelination when transplanted into a model forhuman cell therapy in MS.

So this proteins expression in oligodendrocyteprogenitor cells might ultimately become a therapeutic target,potentially promoting oligodendrocyte formation in MSpatients, said Sim.

The approach also identified several other important candidatesthat play key roles in regulating the development of humanoligodendrocytes.

Other co-authors on the paper are Melanie A. OBara,research scientist; Hani J. Shayya, a UB undergraduate and Karen C.Dietz, PhD, research assistant professor, all of the Department ofPharmacology and Toxicology and Richard A. Seidman, amasters candidate in neuroscience.

The research was funded by the National Multiple SclerosisSoociety, the Kalec Multiple Sclerosis Foundation, the SkarlowMemorial Trust and the Empire State Stem Cell Fund (NYSTEM) throughthe New York State Department of Health.

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Which research results in mice will help humans with MS? Now there's a way to tell - UB News Center

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