Multiple sclerosis lesions fail to remyelinate not because oligodendrocyte precursor cells (OPCs) are dying off, but because those precursor cells are present yet stuck before they mature into myelin-producing oligodendrocytes. Histological studies of the same patient show some lesions repair myelin while others do not, even though OPCs exist in both, pointing to a signaling or differentiation failure rather than a shortage of stem cells. The hosts attribute this stall to the inflammatory environment left behind by immune attacks on myelin, which may confuse or block the local signals precursor cells need to finish differentiating. Because neurons generally cannot be replaced once lost, this breakdown in the natural repair pathway carries lasting consequences.
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The hosts describe histological evidence with red arrows marking repaired lesions and green arrows marking unrepaired lesions in the same individual, showing OPCs are present in both.
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Current disease-modifying therapies (DMTs) can slow further immune damage but cannot force remyelination once axons are already stripped.
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Biogen's monoclonal antibody opicinumab targeted a protein called LINGO-1, which inhibits OPC differentiation, and worked in mice but is noted as an example of the blood-brain barrier complicating translation to therapy.
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The blood-brain barrier, formed by selective endothelial cells, is cited as a major obstacle that has doomed several remyelination-focused therapies.
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26:48>> Um now let's talk about that remission stuff, right? Because you said the there was noticing in the MRI scans, even in these early MRI studies, that it would go down and then it would go up, then it would go down, then it would go up. So certainly, >> which almost feels like an immune response, right? There's something that shows up and then the immune system comes and then it goes away. So there's >> Yeah. And then the immune system maybe like stops paying attention. So then >> comes back. >> So then the myelin comes back. >> So how is the myelin actually coming back right? >> Right. Let's let's let's try to focus in on what is the repair mechanism that is working in healthy patients and what is sometimes working in patients with MS. >> Okay, >> there are there is a mechanism for
27:30spontaneous repair okay >> of the myelin right the brain and the spinal cord they are populated by a reservoir of specialized stem cells called adult oligodendrite precursor cells. These are oligodendrite precursor cells, meaning they are stem cells that could go on to become the oligodendritty that create the myelin, right? >> So, you've got the OPC, and that's the abbreviation that we're going to use from now on. >> Yeah, you know me. You know what OPC? >> What is that from? >> Uh, it's a rap reference. >> Okay, got it. We could. >> All right. Well, I'm going to look it up later. So the OPC this oligodendrite
28:12precursor cell >> can become a mileinating oligodendrite cell >> and there's some pathway right there's some signaling where the stem cell which could become bunch of different things it gets specific signals from its environment to be like oh there's presumably there's like myelin degradation there's some kind of damage I need to go lock in >> become an oligodendrite cell and wrap myself around these axons that no longer have myelin, right? That's the idea. And that's the form of differentiation where it gets some kind of cellular signaling from its environment and then it goes and does a specific job. >> The idea is this is a baby. It's in an egg. It hasn't yet been born. It doesn't
28:52know what it's going to be yet. It could it's like a, you know, and then depending on the context of the environment, >> it can become one thing or another. >> Yeah. Yeah. That's what a stem cell is. And in this case, it becomes this oligodendrite that becomes the myin. It's what's it's what wraps the fruit roll up around the twistler. And this is good. And so the point here being like this is the me mechanism by which the body is generating and when we see the cycling the thing that is going in to then wrap again is this OPC that becomes a uh mileinating uh this oloend >> olodendrite cell. Yes. And and so in healthy patients this is happening all the time.
29:32>> It's fine, >> right? It's happening all the time and it's fine. So what's happening in MS? The first the first um you know hypothesis would be okay maybe the stem cells themselves are dying. >> Okay. >> Right. That's a pretty easy hypothesis, right? There's there's not enough going around. The stem cells with age die off and so you don't have them going around doing this mileinating stuff. >> Your your population is decreasing because you don't have enough babies that can become adults. >> Yeah. Yeah. That's not the case. Okay. People do studies and they actually show that um with histological studies where you can stain certain parts, you can actually see that there are certain lesions within someone who has MS >> where certain lesions in the red arrow
30:15the lesions are fine. >> Mhm. >> They have repaired. But in other lesions like the green arrow in the same individual >> you're getting lesions of MS where there's no myelin and there's no repair. So within the same individual, >> it can't really be possible that like >> that like there's >> there's no oligo dendrites. >> Mhm. >> But somehow there's repair still. >> The repair is still happening because as far as we're aware in this context like that is the that is the mechanism by which the repair happens. >> Yeah. Yeah. So certainly there's oligodendrites that are working, right? >> There's OPC's that are working on the red the progenitor stem cells. The stem cells are working in the red area but not in the green area. Right. >> Right. And if you go and stain and
30:56actually look into it, the green areas have the stem cells. It's just that the stem cells maybe they're not getting the correct type of signaling or maybe they get the correct type of signaling but they can't actually execute. >> And so the point here is is that it's not a lack of of of the the the uh the the the defense like the workers, they're there. >> Yeah. >> Uh but something is breaking down further down in the process. Exactly. And so they're failing to mature into these myelin producing cells >> stuck in adolescence. >> Yes. Yes. In some sense. Um so what's actually happening? Well, it could be
31:36some epigenetic barrier to differentiation. Here we're seeing um immune cells in the yellow actually attacking a myelin cell, an ilodendrite cell. And you can see that as it attacks there's going to be a lot of cellular debris. There's going to be a lot of stress hormones. there's going to be a lot of like random nonsense that is happening and perhaps that environment is making it hard for the illegal dendrites that are around to come in and actually do the repair. Right. >> Right. If there's like a battlefield, >> right? And there's like the I in some sense there's like evidence of a battle. >> Yeah. >> Where a bunch of your homies got knocked out. >> Yeah. >> Like you know, maybe you're like
32:16>> I might go that way. >> Yeah. I might I might not hang out. Right. there the like it's kind of strange to think about but like even individual cells are feeling stress >> from the environment and the macrofasages that usually come in to clean up the battlefield aren't doing their jobs because maybe there's too much >> battlefield debris >> and so perhaps this is the problem right >> and the consequences of this failed rethylation is what it's called >> where you know there's no methylation and then you remethylate >> the the brain The consequences of not doing this, of not remethylating are catastrophic. Namely because
32:57the neurons that you have are the neurons that you have. >> This is why it's super important to have these mechanisms in the nervous system. In other in other organ systems, >> the cells by and large can replicate. Neurons cannot. You are by and large born with the number of neurons that you have. And when a neuron dies, that's it. >> And so just I want to regground myself in kind of the circumstance we've set the table for right now. So you know, in part we have the the neuron itself, right? And the neural pathway is like where the signal is being sent so we can do all of this communication >> and function the way we do.
33:37>> The myelin is this wrapping >> Yeah. >> around it. Uh that has a variety of benefits. >> Yeah. speed, efficiency, >> housekeeping, >> housekeeping. And in MS patients specifically, there is this degradation in this myelin sheath >> that surrounds uh your neurons that gives it all of these added benefits. >> We thought it might have been that the way the the way that they're born, the myelin is the way that it was created, the the there's not enough resource to keep creating it. >> Yeah. that did not seem to be true. Y >> uh and then we moved down the down the
34:18sort of process pipeline and now it's become this idea that um the the environment because there's this constant ebbing and flowing uh of myelin degradation and then the body uh re recreates its myelin sheath in healthy patients but in MS patients that repair process breaks down because of this chaos that is happening in the context text of the battle that creates the mile myelin degradation in the first place. >> Yeah. Yeah. And it seems that the pregentor cells, these stem cells that would go on to create the myelin and repair, they're either confused, they're
34:59not having the right signal. They're getting too much inflammatory signal. Something is happening that is preventing the present workers >> from repairing what they should be repairing. >> And the key idea is like they're there. >> They're there. >> That's the key. >> That's Yeah. is a big point. >> That's a big point. That's a big point. And that's the whole Yeah, that was the whole point of this whole thing, right? Is that they are there. We just need to equip them with perhaps the right signal. >> Okay. >> Okay. >> So, where do the current therapies stand? Well, they can prevent, but they
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