Method Helps Determine Whether Mouse MS Results Affect Humans

“There have been so many failures in clinical trials for MS and other neurodegenerative diseases when promising observations are translated from small animal models to the clinic,” says Fraser J. Sim, PhD, senior author and associate professor in the Department of Pharmacology and Toxicology.

“Our primary motivation was to try to understand, at a molecular level, how the human cells responsible for synthesizing myelin differ from their much-better-studied mouse counterparts.”

“This is an important resource for the field as it allows us to compare human and rodent cells, and it provides a point of reference to understand whether or not gene expression patterns are conserved between species,” explains Sim.

MS and some other neurological diseases occur when there is damage to myelin — the fatty sheath that allows nerve cells to communicate. So the myelin-producing cells, called human oligodendrocyte progenitor cells, or OPCs, found in the brain and spinal cord have been a major focus of efforts to better understand MS and develop potential new treatments for it.

Sim says that undifferentiated OPCs are frequently found in the brain lesions of MS patients, so boosting the differentiation of these cells could lead to myelination and a reduction of symptoms.

One reason why so many clinical trials fail may be because of fundamental differences in the types and levels of genes expressed between mice and humans. Sim and his colleagues addressed this question by performing gene-expression analysis on differentiating human OPCs.

“In this paper, we describe the transcriptional events that underlie how human OPCs develop into oligodendrocytes,” says Sim.

The researchers used a network analysis software tool called weighted gene coexpression network analysis (WCGNA). The software clusters together genes with similar patterns of expression. It also allows for analysis of both conserved and divergent gene expression between humans and rodents.

“WCGNA looks at the relationships between genes rather than absolute differences between conditions in any given experiment,” Sim explains.

He adds that the information encoded in levels of gene expression increasing or decreasing is very reliable and reproducible.

“We performed WCGNA in exactly the same manner on cells isolated from mice, rats and humans, and we prepared these cells in as close to matched conditions as possible, trying to keep things as similar as possible to facilitate this comparison,” says Sim.

It turned out several of the genes the team had identified as relevant to human disease also are involved in mouse development and mouse models of myelin disease.

Based on its findings from that analysis, the team had predicted that GNB4, a protein involved in signal transduction, would be involved in the development of OPCs in humans. The researchers found that over-production of GNB4 could cause human OPCs to rapidly undergo myelination when transplanted into a model for human cell therapy in MS.

“So this protein’s expression in oligodendrocyte progenitor cells might ultimately become a therapeutic target, potentially promoting oligodendrocyte formation in MS patients,” says Sim.

The approach also identified several other important candidates that play key roles in regulating the development of human oligodendrocytes.

Co-first authors are Suyog U. Pol, PhD, now a postdoctoral fellow, and Jessie J. Polanco, a doctoral candidate.

Other co-authors, all of the Department of Pharmacology and Toxicology, are:

• Melanie A. O’Bara, research scientist
• Hani J. Shayya, an undergraduate
• Karen C. Dietz, PhD, research assistant professor

Richard A. Seidman, a master’s candidate in neuroscience, is also a co-author.

The research, “Network-Based Genomic Analysis of Human Oligodendrocyte Progenitor Differentiation,” which was published Aug. 8 in Stem Cell Reports, was supported by the National Multiple Sclerosis Society, the Kalec Multiple Sclerosis Foundation, the National Institutes of Health, the Change MS Foundation, the Skarlow Memorial Trust and the Empire State Stem Cell Fund through the New York State Department of Health.