Making new myelin, have animal studies been sending us in the wrong direction?

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You all know that you can assess how old a tree is by counting the growth rings. You all have heard on carbon-dating, whereby you can assess the age of living things that have died. This works because living things are made of carbon containing molecules.

Carbon comes in a radio-active form called carbon fourteen (related to the number of atoms and electrons in the molecule). This is decaying to form the non-radioactive version carbon twelve and this takes thousands of years. Using carbon dating you can guess the age of a stone-age bone or a tooth.

However in this neat study they apply this idea to looking at the age of individual cells. This is done with help from the extra amount of radioactivity present from nuclear tests in the 1950s.

Radioactive carbon, found as radioactive carbon dioxide, was increased in the atmosphere from testing during the cold war. This is taken up by plants, which we eat and then we use it to make cells. When a cell replicates it needs to make new DNA, which means that radioactive carbon is put into its DNA creating a date stamp for when it was born give or take one and a half years. They can then work out the turnover dynamics of the cells.

To assess the nature of cell generation in multiple sclerosis, they birth-dated mature oligodendrocytes from post-mortem human brain tissue.

In this study there looked for the radioactive carbon in the nucleus of the oligodendrocyte from normal looking white matter and compared it to people with similar birth and death dates who didn’t have MS who were born before or after the nuclear bomb tests.

Looking at cells born before they got MS they looked like the non-MS tissue, but after the development of MS there were many more oligodendrocytes created notably in those people with very aggressive MS although this feature was variable and seen in people without rapid progression.

They then looked in areas where there was myelin repair, called a shadow plaque. There they found few younger myelin forming cells and this was similar to the number found in healthy white matter (bit containing the myelin sheaths). The bombshell they drop it that the repairing oligodendrocytes came from oligodendrocytes made before the MS lesion rather than new ones, which they think would form less than 5% oligodendrocytes in the remyelinated area.

The old oligodendrocytes occurred at similar levels to nearby healthy tissue thus contrasting with animal models, importantly they suggest that those replacing the myelin were old cells not coming from new oligodendrocyte precursor cells. So the important message is that remyelination may occur as long as the oligodendrocyte is surviving and not lost. This says that we have to protect what is there as soon as possible.

We have spent a lot of effort trying to work out how to get oligodendrocyte precursor cells to proliferate to make more of themselves and importantly we have been pumping huge resource into making the precursor cell differentiate into an adult myelinating cell based on thoughts from animal studies. The inference is that this is an animal based idea that may not be relevant to the human.

Dynamics of oligodendrocyte generation in multiple sclerosis

Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process. Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans5, it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of 14C derived from nuclear testing in genomic DNA1, we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques—thinly myelinated lesions that are thought to represent remyelinated areas—were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.

Therefore it will be interesting to see what the myelin-makers have to say about this study and perhaps we can get Prof Franklinstein or ffffffrench constant to give their take and see how they explain these results. There may be explanations that I haven’t thought of .

Have the pathologists been missing the oligodendrocyte precursor cell driven repair because they were fixated on shadow plaques (which they think is the repairing lesion)?

Wouldnature do something so fundemental to make humans diferent from other animals?

To see the potential difference between animals we can look at

Sequential Contribution of Parenchymal and Neural Stem Cell-Derived Oligodendrocyte Precursor Cells toward Remyelination.

Serwanski DR, Rasmussen AL, Brunquell CB, Perkins SS, Nishiyama A.

Neuroglia. 2018 ;1(1):91-105. 

In the adult mammalian forebrain, oligodendrocyte precursor cells (OPCs), also known as NG2 glia are distributed ubiquitously throughout the gray and white matter. They remain proliferative and continuously generate myelinating oligodendrocytes throughout life. In response to a demyelinating insult, OPCs proliferate rapidly and differentiate into oligodendrocytes which contribute to myelin repair. In addition to OPCs, neural stem cells (NSCs) in the subventricular zone (SVZ) also contribute to remyelinating oligodendrocytes, particularly in demyelinated lesions in the vicinity of the SVZ, such as the corpus callosum. To determine the relative contribution of local OPCs and NSC-derived cells toward myelin repair, we performed genetic fate mapping of OPCs and NSCs and compared their ability to generate oligodendrocytes after acute demyelination in the corpus callosum created by local injection of α-lysophosphatidylcholine (LPC). We have found that local OPCs responded rapidly to acute demyelination, expanded in the lesion within seven days, and produced oligodendrocytes by two weeks after lesioning. By contrast, NSC-derived NG2 cells did not significantly increase in the lesion until four weeks after demyelination and generated fewer oligodendrocytes than parenchymal OPCs. These observations suggest that local OPCs could function as the primary responders to repair acutely demyelinated lesion, and that NSCs in the SVZ contribute to repopulating OPCs following their depletion due to oligodendrocyte differentiation.

So we have precursors forming precurosrs forming myelinating cells from dividing and differentiating to for adult cells from young cells. Is this like human cells?

The human cells however have just got more complex

Altered human oligodendrocyte heterogeneity in multiple sclerosis

  • Sarah Jäkel et al  Nature. 2019
    Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases as OLs both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system (CNS) thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, suggesting that other factors contribute to this variability. One such factor may be OL heterogeneity. Not all OLs are the same—mouse spinal cord OLs inherently produce longer myelin sheaths than cortical OLs2, and single-cell analysis of mouse CNS identified further differences3,4. However, the extent of human OL heterogeneity and its possible contribution to MS pathology remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and MS patients. We identified sub-clusters of oligodendroglia in Ctr human WM, some similar to mouse, and defined new markers for these cell states. Strikingly, some sub-clusters were under-represented in MS tissue, while others were more prevalent. These differences in mature OL sub-clusters may indicate different functional states of OLs in MS lesions. Since this is similar in normal appearing white matter (NAWM), MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important to understanding disease progression and developing therapeutic approaches.

About the author

MouseDoctor

10 comments

  • Well well, I wonder how this revelation is going to go down in Cambridge/Edinburgh?
    An outstanding piece of work that reveals some uncomfortable truths.

  • 1. So is it, prevent or suck it?
    2. PPMS patients suffer from neurodegeneration, but not much demyelination. Could looking at OL be an old-school approach?
    I know you are a firm supporter of remyelinating agents to support your MS drug pyramid, but I tend to believe it is a waste of time and money. With the drugs we have we can block demyelination however this would not stop MS neurodegeneration. Research should look elsewhere.

  • Very interesting…

    Maybe MS is a problem in the earliest stages with oligodendrocytes and has nothing to do with the immune system at all initially. Then the immune system generates an unhelpful response. ???

    Other animals can be neurologically very different. As far as I know, some birds have brain regions that shrink/regenerate according to the season. Logical – what use is energy hungry neural circuitry for singing complex songs outwith the breeding season?

    • Not exactly sure, I’ll see if I can get MD2 sorted as we have a profile and it can be put in there. They tried to may be get a gravitar which i found very annoying and was told that MouseDoctor and ProfMouse were alreaady taken

  • Actually we don’t need to wait for Comments as the the Edinburgh Group (Prof fffffrench Constant in the I jjust had to do more reading as Nature paper above, say

    “Furthermore our data show the need to re-evaluate current approaches for discovering regenerative therapies in MS. These are based on the assumption that enhancing differentiation of resident OPCs to OLs expressing myelin genes/proteins will lead to enhanced remyelination in progressive MS. Our results show that this is over-simplistic for two reasons. First, the striking pathology we observe is not a failure of dif-ferentiation to the myelin gene-expressing OL, but is instead the loss of the Oligo1 population (which we predict to be fully mature and stable OLs) and the skewing of the differentiation program to other subclasses of mature OLs with different transcriptional signatures”.

    Therefore the same thing being said by the Swedish group is being said by the Edinburgh/swedish group.

    • They further say “This is in line with retrospective carbon 14 based birth-dating in MS patients22and electron microscopy in large animal models23, but in sharp contrast to rodents where remyelination is driven entirely by recruitment and differentiation of resident OPCs. This highlights the difficulties in extrapolation from rodent to human and further emphasizes the power of studying human pathology at a single cell level to inform appropriate therapeutic approaches”

      So where does this bombshell leave us. Rodents have suggested trials for remyelination. The results were not earth shattering, rodent studies have suggested a reason for this but surely this study would suggest that it is time to call time on such animal studies

  • Loll

    Those are the studies i post in The Q&a session some days ago..:):):)

    Thanks for review

    Have´nt not read it yet

    Obrigado

  • > Carbon comes in a radio-active form called carbon fourteen (related to the number of atoms and electrons in
    > the molecule).

    Just a slight correction here. The mass of Carbon-14 or 14C–an atom–is related to the number protons (6) and neutrons (8). Electrons should equal the number of protons and have negligible mass.

    Other than that, a great post.

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