Microglial phagocytosis of oligodendrocyte progenitor cells: The future of therapeutic strategies for multiple sclerosis?

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It is becoming increasingly clear that microglia are crucial for proper brain function and development. Dr Tara DeSilva, Associate Professor at the Cleveland Clinic and Case Western Reserve University School of Medicine, funded by the National Institutes of Health, the National Science Foundation, and the National Multiple Sclerosis Society, has recently investigated the role of microglia in brain development. Interestingly, it was found that microglial engulfment of oligodendrocyte progenitor cells, which will later form the insulation around neuronal axons, is crucial for proper myelination in adulthood. These results provide a potential role for microglia as a target for remyelinating therapies.

Neurons are responsible for transmitting information by conducting electrical impulses to communicate with other neurons using specialised connections called synapses. Glia cells, mainly consisting of oligodendrocytes, microglia, and astrocytes, far outnumber neurons and perform diverse roles necessary for neuronal function. Myelin is comprised of oligodendrocytes that form the insulation around neuronal axons or nerve fibres and is essential for the proper speed of electrical impulses. Microglia are resident immune cells in the brain. They become activated in neuroinflammatory diseases, such as stroke, neurodegeneration, and traumatic brain injuries. Microglia also carry out surveillance within the brain and are crucial for its protection. Additional roles for microglia occur during brain development, where they monitor and control the populations of neurons to ensure that proper neuronal connections are formed. Astrocytes also become activated in neuroinflammatory conditions and neurodegeneration, but also have important roles in neuronal function as they are closely associated with synapses and can release molecules in response to activity.

The role of microglia within development
To further investigate the role of microglia during development, Dr Tara DeSilva, and her team at the Cleveland Clinic and Case Western Reserve University School of Medicine, have used a series of cutting-edge animal and neuroimaging techniques.

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In order to study cells within the developing mouse brain, transgenic (altered) mouse lines were used. In this case, the mice have been bred to express green fluorescence in microglia and red fluorescence in oligodendrocyte progenitor cells. Oligodendrocyte progenitor cells are the cells present during development which later form adult oligodendrocytes that comprise the myelin sheath. Under a fluorescent microscope, these different cell populations can be easily visualised.

The group found that monitoring the movement and shape of the microglia in the corpus callosum across a range of post-natal ages revealed interesting features. The corpus callosum is a bundle of nerve fibres located within the brain which allows communication between the right and left hemispheres. At four days old, the green-fluorescent microglia appear to have bushy processes, almost broccoli-like. The shape of microglia then changes to become ameboid – a rounded shape with minimal processes or extensions. When the mice are seven days old, amoeboid microglia move over to the oligodendrocyte progenitor cells and engulf them via phagocytosis. As the days go on, the microglia appear to become less rounded, and by day 15 they have the classic ramified morphology typical within an adult brain. The ability of microglia to phagocytose cells, debris, and invading pathogens is a classic function of microglia. In the adult brain, phagocytosis is a crucial mechanism by which the cells engulf and essentially eat harmful things such as pathogens or dead cells. However, this is the first documentation of microglial phagocytosis of oligodendrocyte progenitor cells during development.

“The group found that monitoring the movement and shape of the microglia across a range of post-natal ages revealed interesting features.”

Microglial phagocytosis of the oligodendrocyte progenitor cells is clearly an important step in brain development as it was calculated that over half of the amoeboid microglia at day seven were phagocytosing oligodendrocyte progenitor cells. Phagocytosis is usually triggered because the cells to be consumed send out an ‘eat me’ signal to indicate that they are stressed or dying. Interestingly, this was found not be the case with the majority of oligodendrocyte progenitor cells which were being phagocytosed.

The myelin sheath wraps around a neuron’s axon, an insulated cable that allows the brain signals to propagate much faster. Designua/Shutterstock.com

This process was more closely examined using a technique called ex vivo time-lapse imaging. To put it simply, this technique is used to create a time-lapse video of the phagocytosis events happening within the tissue. These videos captured two main interactions between the microglia and oligodendrocyte progenitor cells. The microglia either inspect the oligodendrocytes a few times and move on, or they inspect and engulf via phagocytosis. These progenitor cells were once again not presenting an ‘eat me’ signal and appeared healthy prior to being eaten. So why do the ameboid microglia engulf viable oligodendrocyte progenitor cells?

The role of oligodendrocytes
Oligodendrocytes are an important cell type within the central nervous system as they form what is known as a myelin sheath. Myelin sheaths wrap around part of a neuron’s axon, creating an insulated cable that allows the brain signals to propagate much faster. This is because the sheath doesn’t cover the entire axon. The gaps between the sheaths are called ‘nodes of Ranvier’. This arrangement causes the brain signals, or action potentials, to jump from node to node, rapidly increasing the rate of signalling.

Microglia engulfing oligodendrocyte progenitor cells.

The importance of these sheaths can be demonstrated by the debilitating pathology seen in multiple sclerosis (MS). MS is caused by an individual’s own immune system mistaking the myelin sheath for a foreign pathogen and attacking it, causing loss of the sheath which affects brain signalling. This causes symptoms such as loss of vision, paralysis, and lack of muscle coordination, to name a few. The condition eventually results in death and there are currently no good treatment options. This condition is particularly distressing as it is most common in young adults.

“These results indicate that microglia are crucial during brain development to ensure that oligodendrocytes adequately myelinate axon fibres
in the adult brain.”

White matter of the brain is mainly composed of nerve fibres and their myelin sheaths. During white matter development, certain molecular markers can be used to identify the stage the oligodendrocytes are in – for example, if they are pre-myelinating and immature or if they are more mature and ready to begin myelinating by forming the axonal sheath. Examination of these markers by DeSilva and her team indicate that the majority of the oligodendrocytes which are engulfed by the microglia when mice are seven days old are in fact pre-myelinating (immature). This finding was important as it allowed the group to investigate if they could block this phagocytosis.

High-powered imaging with microglia engulfment of an oligodendrocyte progenitor cell.

In order to block the ability of microglia to phagocytose oligodendrocyte progenitor cells, transgenic mice were used. These mice were deficient in the fractalkine receptor, which is expressed on microglia and known to regulate their ability to trigger phagocytosis. These mice had a significant reduction in phagocytosis, demonstrating that microglia engulfment of oligodendrocyte progenitor cells is dependent upon fractalkine receptor signalling. During early adulthood (aged 30 days), these animals had a greatly increased number of mature oligodendrocytes. Interestingly, the mice also had a thinner myelin sheath compared with normal mice. Therefore, it appears that microglia engulfment of oligodendrocyte progenitor cells regulates myelination in the central nervous system by controlling the ratio of cells to neuronal axons.

Why is this important?
These results indicate that microglia are crucial during brain development to regulate the proper number of oligodendrocytes and ensure that they adequately myelinate axon fibres in the adult brain. It may be that developmental phagocytosis is essential to stop oligodendrocytes from overcrowding axon nerve fibres and preventing proper myelination. This finding holds hope for future MS treatments as it seems that microglial regulation is required for proper myelination. It could be that the mechanism can be stimulated to trigger re-myelination after the onset of MS symptoms, or that individuals who later develop MS have some developmental abnormality during microglial phagocytosis of oligodendrocyte progenitor cells. Regardless, this research offers an important preliminary result which could hold strong potential for the future of MS treatment.

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Do you plan to carry out the same experiments in mouse models of multiple sclerosis to see if fractalkine-dependent microglial phagocytosis is altered?

In neuroinflammatory demyelinating diseases like MS, new oligodendrocyte progenitor cells proliferate but do not form myelin as they normally would during development. We hypothesise that microglia are altered during neuroinflammation and do not phagocytose oligodendrocyte progenitor cells, thus due to overcrowding, new myelin formation does not occur. Therefore, we will explore the signalling processes needed for microglial phagocytosis of oligodendrocyte progenitor cells and explore how this mechanism can be reinstated during neuroinflammatory demyelination to promote regeneration of myelin.

 

References

  • Nemes-Baran, AD, White, DR, DeSilva, TM, (2020) Fractalkine-dependent microglial pruning of viable oligodendrocyte progenitor cells regulates myelination. Cell Reports 32, 108047. doi.org/10.1016/j.celrep.2020.108047
DOI
10.26904/RF-139-1965671004

Research Objectives

Dr DeSilva and her team study adult demyelinating diseases, such as multiple sclerosis.

Funding

This study was supported by National Multiple Sclerosis Society RG 4587-A-1, National Science Foundation 1648822, and the National Eye Institute RO1EY025687. The work used a Leica SP8 confocal microscope, purchased with funding from National Institutes of Health SIG grant 1S10OD019972-01.

Bio

Tara M DeSilva, PhD, is an associate professor at the Cleveland Clinic and Case Western Reserve University School of Medicine, and serves as Vice Chair for the Department of Neurosciences. Dr DeSilva received her PhD from the University of Pennsylvania and completed her postdoctoral training at Children’s Hospital Boston, Harvard Medical School.

Tara M DeSilva

Contact
Department of Neurosciences
Lerner Research Institute (NB3-087), Cleveland Clinic
9500 Euclid Avenue, Cleveland Heights
OH 44195, USA

E: desilvt@ccf.org
T: +1 216 217 6107
W: www.lerner.ccf.org/neurosci/desilva

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