Which research results in mice will help humans with multiple sclerosis? Now there's a way to tell

August 15, 2017 by Ellen Goldbaum
Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100. Credit: Marvin 101/Wikipedia

People with multiple sclerosis (MS) know all too well the frustration of hearing that success in treating the disease in mice had little or no effect in humans.

Unfortunately, with no large animal models for MS, results that suggest promising new treatments in mice often are ineffective in humans.

Now, University at Buffalo researchers have developed and successfully tested a method for determining how relevant to the human disease findings are from mouse models. The research was published Aug. 8 in Stem Cell Reports.

"This is an important resource for the field as it allows us to compare human and rodent cells, and provides a point of reference to understand whether or not gene expression patterns are conserved between species," said Fraser Sim, PhD, senior author and associate professor in the Department of Pharmacology and Toxicology in the Jacobs School of Medicine and Biomedical Sciences at UB. Co-first authors are Suyog U. Pol PhD, now a postdoctoral 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 for MS when promising observations are translated from small animal models to the clinic," Sim said. "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."

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 explained 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.

From OPCs to oligodendrocytes

One reason why so many fail may be because of fundamental differences in the types and levels of 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," said Sim.

To do it, they 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 said.

He added 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 prepared these in as close to matched conditions as possible, trying to keep things as similar as possible to facilitate this comparison," said 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.

New myelin-repairing gene

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, a protein involved in the transduction of extracellular signals, 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 might ultimately become a therapeutic target, potentially promoting oligodendrocyte formation in MS patients," said Sim.

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

Explore further: Enzyme in myelination process could lead to better understanding of neurological disorders

More information: Suyog U. Pol et al. Network-Based Genomic Analysis of Human Oligodendrocyte Progenitor Differentiation, Stem Cell Reports (2017). DOI: 10.1016/j.stemcr.2017.07.007

Related Stories

Enzyme in myelination process could lead to better understanding of neurological disorders

April 14, 2016
The removal of the enzyme Dnmt1 during oligodendrocyte progenitor cell (OPC) differentiation in the central nervous system resulted in inefficient myelin formation and neurological deterioration, including loss of control ...

Hidden herpes virus may play key role in multiple sclerosis, other brain disorders

July 10, 2017
The ubiquitous human herpesvirus 6 (HHV-6) may play a critical role in impeding the brain's ability to repair itself in diseases like multiple sclerosis. The findings, which appear in the journal Scientific Reports, may help ...

Mice stem cells guided into myelinating cells by the trillions

September 25, 2011
Scientists at Case Western Reserve University School of Medicine found a way to rapidly produce pure populations of cells that grow into the protective myelin coating on nerves in mice. Their process opens a door to research ...

MicroRNA treatment restores nerve insulation, limb function in mice with multiple sclerosis

March 27, 2017
Scientists partially re-insulated ravaged nerves in mouse models of multiple sclerosis (MS) and restored limb mobility by treating the animals with a small non-coding RNA called a microRNA.

'Master switch' for myelination in human brain stem cells is identified

June 30, 2014
Scientists at the University at Buffalo have identified the single transcription factor or "master switch" that initiates the critical myelination process in the brain. The research will be published online in Proceedings ...

Recommended for you

Touching helps build the sexual brain

September 21, 2017
Hormones or sexual experience? Which of these is crucial for the onset of puberty? It seems that when rats are touched on their genitals, their brain changes and puberty accelerates. In a new study publishing September 21 ...

Gene immunotherapy protects against multiple sclerosis in mice

September 21, 2017
A potent and long-lasting gene immunotherapy approach prevents and reverses symptoms of multiple sclerosis in mice, according to a study published September 21st in the journal Molecular Therapy. Multiple sclerosis is an ...

Neuron types in brain are defined by gene activity shaping their communication patterns

September 21, 2017
In a major step forward in research, scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Cell a discovery about the molecular-genetic basis of neuronal cell types. Neurons are the basic building blocks that ...

Your neurons register familiar faces, whether you notice them or not

September 21, 2017
When people see an image of a person they recognize—the famous tennis player Roger Federer or actress Halle Berry, for instance—particular cells light up in the brain. Now, researchers reporting in Current Biology on ...

Highly precise wiring in the cerebral cortex

September 21, 2017
Our brains house extremely complex neuronal circuits whose detailed structures are still largely unknown. This is especially true for the cerebral cortex of mammals, where, among other things, vision, thoughts or spatial ...

Faulty cell signaling derails cerebral cortex development, could it lead to autism?

September 20, 2017
As the embryonic brain develops, an incredibly complex cascade of cellular events occur, starting with progenitors - the originating cells that generate neurons and spur proper cortex development. If this cascade malfunctions ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.