Jeffrey Huang, PhD, Talks Remyelination Strategies in Multiple Sclerosis

In this podcast, Dr Huang discusses various research models that he, his colleagues, and others are currently using to examine potential remyelination strategies for multiple sclerosis (transcript below). Dr Huang recently gave a talk about this topic at the American Neurological Association's 145th Annual Meeting.

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Jeffrey Huang, PhD, is an associate professor in the department of biology and Deputy Director of the Center for Cell Reprogramming at Georgetown University in Washington DC.

Huang J. Strategies to promote remyelination. Talk presented at: ECTRIMS/ACTRIMS MSVirtual2020. September 13, 2020.


Christina Vogt: Hello, everyone, and welcome back to another podcast. I'm Christina Vogt, managing editor of Neurology Learning Network. Today, I'm joined by Dr Jeffrey Huang, who is an associate professor in the Department of Biology at Georgetown University in Washington DC.

Today, we'll be discussing remyelination strategies in multiple sclerosis, a topic he recently discussed at MSVirtual2020. Thank you for joining me today, Dr Huang. So first, where does research stand now in regards to central nervous system repair after a demyelinating injury in MS?

Dr Jeffrey Huang: There are a lot of interesting findings in the last few years understanding the mechanisms of remyelination, and this is the process in which oligodendrocytes regenerate following demyelinating injury and remyelinate axons.

We're learning more and more about the mechanisms with regards to how it differentiates. The mitral oligodendrocytes themselves might play a role in remyelination as well.

There's a lot of progress in terms of understanding how remyelination is achieved, particularly in animal models. Recently, there are some promising drugs that might be able to promote myelination. One of them is clemastine, who was identified through a screen by Jonah Chan's group at UCSF.

This is pretty exciting. It seems to promote remyelination very well in culture as well as in animal models. There are some promising data from clinical trials.

There's also a study done by Robin Franklin's group at the University of Cambridge in the UK that shows that the anti‑aging drug, metformin, seems to be able to improve remyelination deficiency in aged animals. This is really exciting because metformin is available to patients.

There's also suggestion that MS may be a disease of accelerated aging, so drugs that might be able to counter age‑associated impairment in myelination may be beneficial to MS. That study came out about a year or 2 ago, and that was really exciting and promising.

So, with regards to the question, "Where does research stand?" I think we're learning every day, and we're learning not just about the mechanism of remyelination but, how does the environment, the aging environment, play a role in remyelination?

Finally, there's another really interesting study from Danny Reich's group at the NIH that has been able to track these chronic active, smoldering lesions in MS patients and using advanced MRI techniques.

Now, these lesions are relatively stable, and they may even be expanding. The reason they're smoldering is because they're sort of slowly expanding. They're characterized by these high density macrophages at the rims of the lesions. They're sometimes also called rim lesions.

What Danny Reich's group along with Martina Absinta, who was the first author of the work, they have found that if MS patients have increasing numbers of these chronic active, smoldering lesions, these seem to correlate with disease worsening.

So, this tells us a lot about how the injury environment, the lesion environment that's characterized by chronic inflammation may be actually damaging or may contribute to disease progression. If you look at the pathology of these lesions, what essentially you'll see is high density of macrophages, ongoing demyelination, and incomplete remyelination.

When you think about repairing myelination, it is very important to be able to reduce these rim lesions from forming or from continuing to expand. That means if you could target inflammation within the brain, targeting these macrophages, this might actually be beneficial to promoting repair in the CNS.

Essentially, when you're thinking about remyelination in multiple sclerosis, I think you need to take a number of different angles. There's the potentially aging environment. There's the chronic inflammatory environment in the lesion, and then there's the intrinsic problem within oligodendrocytes that somehow may not be able to allow them to differentiate or remyelinate properly. A 3‑pronged or a multi‑angle approach is probably the best way to repair in multiple sclerosis.

Christina Vogt: Could you discuss the research models you, your colleagues, and others are using to examine this?

Dr Huang: Now, with regards to the research models, there are a number of research models, animal models, mouse models, that are used in multiple sclerosis. None of them are exactly like multiple sclerosis, but they could capture various aspects of disease pathology.

So, when you think about animal models, you kind of have to ask, which aspect of the disease do you really want to study? We use a model called lysolecithin demyelination. Essentially, this is a highly tractable and reproducible demyelination model in mouse where we could induce a focal injury or demyelinating injury in the mouse central nervous system.

Whether it's the spinal cord or in the corpus callosum, you have this focal lesion where myelin is destroyed, and then over time, a reproducible time point, the oligodendrocyte precursors are able to come into the lesion, differentiate, and remyelinate axons.

This allows us to track the injury microenvironments as well as the signals within oligodendrocyte lineage cells that are undergoing a regeneration and remyelination. So, we find that a very useful model, particularly to study remyelination.

Other people have used models like cuprizone, which is a diet‑induced intoxication study method where mice are fed this cuprizone‑enriched diet, and over time, about 6 weeks or so, they exhibit demyelination in the corpus callosum. Then, when you remove cuprizone diet, they start to remyelinate.

It is pretty useful, but the difference is that in this model, there's no clear blood‑brain barrier breakdown, so there's no peripheral immune response that contributes to remyelination in the corpus callosum cuprizone model.

There are a number of reasons why we don't use this model. For one thing, the corpus callosum axons are not 100% myelinated. It's partially myelinated, probably about 50%. So, when you demyelinate and assess remyelination, you can't be certain that this is actually remyelination or de novo myelination where new myelin is being laid on axons that were previously not myelinated.

That's one thing, and the other thing is that the axons in the corpus callosum are very thin. So, compared to the spinal cord, for example, where remyelinated axons display a very distinctive membrane morphology compared to myelin that has not been damaged, they're much thinner.

It's very easy to distinguish a remyelinated axon from a myelinated axon. In the corpus callosum, it's much tougher just because axons are so thin. That said, it doesn't mean it's a bad model. It is still a very commonly used model.

Finally, another model that is commonly used and traditionally used for multiple sclerosis research is experimental autoimmune encephalomyelitis or EAE. There are different types of EAE models, but in general, you'd use autoimmune demyelination in mice, and this results in profound demyelination and axonal injury, particularly in the spinal cord.

So, because the damage, the lesions in the spinal cord, is pretty widespread, it's very hard to track remyelination in this model. Traditionally, this model has been very useful to study the role of peripheral immune cells in disease development or disease progression.

They sort of display this increasing disability over time, starting with a limp tail to hind limb paralysis. You can sort of see this over time. If you have an immune‑modulatory drug that targets T cells, for example, you could stop the development of the disease or even prevent them from getting to the peak of the disease, peak of disability.

So that's been very useful, but it's not an ideal model to study remyelination just because it's much harder to track remyelination in these models. What we do, though, in our lab is we combine both lysolecithin model and the EAE model because our lab is particularly interested in the role of inflammation in remyelination.

We do use the lysolecithin model to really examine how macrophages or microglia play a role in remyelination and the factors involved in either preventing oligodendrocyte differentiation or promoting oligodendrocyte differentiation.

Then we use the EAE model to really examine the immune response or the inflammatory response or how they're associated with clinical score or disease development in these mice. The question there is not to ask about remyelination but just ask what happens to these mice if we can modulate the immune response.

Christina Vogt: What areas of future research are needed in this field?

Dr Huang: With regards to research that are still needed, I think the recent finding about metformin and how MS may be a disease of accelerated aging—there's some evidence for this as well—we need to start to think about MS not just as simple as, how do we promote oligodendrocyte differentiation either in culture or in young animals? We need to start to think about maybe aged animals or, how does the aging environment impact remyelination?

Then the other thing that I think is really important is the finding that accumulation of chronic active, smoldering lesions in brain of MS patients correlates with increased disability. I think that's very important.

This is where I think, if we want to find a way to prevent disease progression, we really need to start looking at these chronic active lesions. Why are they there, why do they increase with disease, and how do they prevent repair?

Is there any way we could stop macrophage expansion or activation in multiple sclerosis? Can we target these cells so that we could get a much more favorable environment for remyelination to occur?

So, I think that's where we should be going, but again so much great stuff has been done in the recent years on understanding the mechanism of oligodendrocyte differentiation and remyelination as well as drug targets for stimulating oligodendrocyte differentiation and remyelination.

We're just sort of adding more complexity now to remyelination research by incorporating the aging environment, the lesion microenvironment associated with inflammation. All of those things are playing a critical role in remyelination success. There's also now studies suggesting astrocytes in the injury environment play an important role in remyelination success.

We need to really look at all of the cell types within the injury environments and their contribution to the success of remyelination in order to have an effective drug to promote repair in multiple sclerosis.

Christina Vogt: Lastly, what key takeaways about this research do you hope to leave with neurologists, neurology providers, and researchers?

Dr Huang: In terms of the research world, we're moving quickly. We're starting to understand the lesion microenvironment better. We're starting to identify drugs that promote remyelination as well as pathways that are relevant or crucial for remyelination both in culture as well as in animal models.

I'm pretty hopeful. I mean, we're already moving pretty quickly, I think, at least in the right direction in terms of research in MS. I think one of the good things about MS is that there are already many good disease‑modifying drugs that seems to be able to stabilize the disease.

What we are interested in, I think what a lot of patients are concerned about is, how do you prevent progression? You may be on these disease‑modifying drugs, but still many patients continue to progress, so we need to start to think about not just the immune system but what is happening in the brain, the lesion environment in the brain.

This involves microglia and macrophages that are in the brain, oligodendrocyte lineage cells, including precursors and mitral oligodendrocytes, as well as astrocytes. They're all in the lesioned environment, so we need to start to understand those things. That's where, I think, research is going so that we could develop a better picture of how to improve remyelination.

I'm pretty confident we're going to get there. I think there are a lot of great research groups out there who have been working on this and who are really pushing the field forward.

Christina Vogt: Thanks again for joining me today, Dr Huang. For more podcasts like this, visit