The Role of Chemokines and their Receptors in Directing the Migration and Function of Neural Stem Cells in Experimental Autoimmune Encephalomyelitis

Richard Miller, Ph.D.

Northwestern University Feinberg School of Medicine

Funded in December, 2006: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Can Chemokine Receptors Direct White Blood Cells to Repair Damaged Myelin in Multiple Sclerosis?

Investigators will examine whether proteins called “chemokines” can direct certain stem cells in the brain to sites where myelin, the sheath surrounding nerve cell axons in the brain and spinal cord, has been damaged in the autoimmune disease multiple sclerosis (MS).  If so, the stem cells, once mature, could repair the damaged myelin.   

In MS, immune cells mistake myelin as foreign, and cross the blood-brain-barrier to attack it, producing inflammation. Most current MS therapies, therefore, act to suppress this inflammatory response.  An alternative approach may be even more effective, according to researchers, based on recent evidence that chemokines (protein compounds on the surface of cells) can guide cells to their destination.  Chemokines are known to direct immune cells to sites of inflammation, and recent studies in the animal model of MS, called experimental autoimmune encephalomyelitis (EAE), indicate that levels of chemokines and their receptors are increased during acute exacerbations of symptoms in EAE. Surprisingly, the researchers have found, chemokine receptors occur in neurons, in glial cells that interact with neurons to produce the myelin sheath, and in the stem cells that are the progenitors of neurons and glial cells.  These findings suggest that chemokines can guide these cells to specific destinations as well. 

The researchers hypothesize, therefore, that chemokines at sites of myelin damage might be able to direct stem cells that destined to become glial cells to these damaged sites.  If so, these cells then could help repair the myelin damage. They will test this hypothesis in the EAE animal model of MS by defining the signaling of progenitor glial cells in two ways.  They will inject and transplant into the EAE mice glial progenitor cells grown in tissue culture, and they will ask how chemokines act on the endogenous population of glial progenitor cells residing in the mouse brain. They also will determine whether, once signaled, these endogenous progenitor cells migrate to the sites of myelin inflammation. 

Significance: By defining the role of chemokine signaling in the animal model of MS,and seeing whether chemokines can direct glial stem cells to sites of inflammatory damage of myelin to repair this damage, the research may lay the groundwork for developing an entirely new therapeutic approach to autoimmune MS.

ABSTRACT

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The Role of Chemokines and their Receptors in Directing the Migration and Function ofNeural Stem Cells in Experimental Autoimmune Encephalomyelitis

It is currently thought that neural stem and progenitor cells may be useful in the repair of different types of brain damage. For example, it is thought that oligodendrocyte progenitors (OPs) may be able to remyelinate white matter in brain-demyelinating diseases such as multiple sclerosis. In order to achieve this aim, it is important to understand how transplanted or endogenous OPs can migrate to areas of demyelination, and what factors influence their survival and allow these cells to engage in successful remyelination.

In this proposal we shall investigate the possibility that chemokines, synthesized by cells in the inflamed white matter, help to guide the migration of OPs to sites where they can potentially engage in remyelination. We have demonstrated that OPs express numerous types of chemokine receptors and that chemokines can act as chemoattractants for these cells. We shall examine the migration of OPs transplanted into the brains of mice with Experimental Autoimmune Encephalomyelopathy (EAE), a widely used model of MS, to see if they migrate into the white matter. Using OPs from different types of chemokine receptor ko mice will allow us to answer the question as to whether chemokines are involved in directing OP migration. Studies using transgenic reporter mice expressing chemokine receptors and EGFP will help us to analyze whether chemokines direct the migration of  endogenous OPs.  Overall, these studies should provide important information concerning the potential therapeutic use of OPs in demyelinating diseases.

INVESTIGATOR BIOGRAPHIES

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Richard Miller, Ph.D.

Dr. Richard J. Miller is an Alfred Newton Richards Professor in the Department of Molecular Pharmacology and Biological Chemistry at the Northwestern University Feinberg School of Medicine.  He obtained his Ph.D. at the University of Cambridge in the United Kingdom in 1975. Dr. Miller's research interests are in understanding the molecular basis of the way nerve cells communicate with each other and with other types of cells. For example, how do these processes help us to explain communication in the brain under normal conditions and in the context of brain diseases?

In order to carry out these aims, Dr. Miller's laboratory carries out research on neuronal receptors and ion channels.  He is currently carrying out investigations on the action of chemokines and cytokines in the brain.  In particular, he is interested in the possibility that these molecules help direct the processes of neurogenesis and oligodendrocyte formation that are important in neurodegenerative and demyelinating diseases such as Parkinson's disease and multiple sclerosis.