Welcome to this iBiology seminar, my name is Mikael Simons.
And I will speak about myelination, remyelination, and multiple
sclerosis. So this seminar is divided into two parts, I will start
and give an overview about progressive multiple sclerosis, myelination,
and remyelination. And Christine Stadelmann will then take over
and talk about the neuropathology of multiple sclerosis.
So, just to remind you, multiple sclerosis is an autoimmune disease
that leads to an inflammatory attack probably against the myelin sheath
that results in multifocal inflammatory lesions that you can see
here in the MRI by these white spots. These hyperintense lesions are then
highlighted in the neuropathological images, and you can see here
the three hallmarks of M.S. The first is inflammation, so there is
infiltration of B-cells and T-cells, and in particular, macrophages.
The second hallmark is demyelination, you can see myelin in blue
and the completely demyelinated area in white. The third hallmark
is axonal loss, so in the lesion there's also partial axonal damage
or injury. The typical MS clinical course is shown here, so typically it
starts as a relapsing remitting disease, where patients develop symptoms and then
they recover from these relapses at least partially, and this is
repeated over and over again. Until the one or two decades or so,
when the disease then converts into secondary progressive MS.
There are two extreme forms of this, one is relapsing remitting MS
without progression into secondary progressive MS, and the other extreme is
primary progressive MS, where there is no relapses and the patients
immediately start with the progressive phase. So in this progressive phase,
the symptoms that the patient develops are irreversible. Now while there are good
treatment options for relapsing remitting MS, the treatment for secondary progressive
MS, or primary progressive MS, is not possible. So therefore,
it is important to understand how progressive MS develops.
So if you look at the pathology, then the acute focal lesions decrease
gradually over time. However, there is a second pathology which
increases. This is the global or diffuse pathology. And this consists of
widespread neurodegeneration or a diffuse inflammation. Now a key question is
to understand how the focal pathology can convert into a global
diffuse pathology. So how this really happens is not known.
I can just present a few ideas here of how the pathology spreads.
So the white box here is the brain, and you have four inflammatory
lesions within this brain. Now some of these lesions may resolve
inflammation, may disappear over time, while in other lesions, the inflammation
may persist. And this can serve as the nucleus where immune cells may
enter or infiltrate the brain. In addition, the immune cells from the
periphery may enter the brain from the edges of the meninges into the brain.
So at the end you have a focal inflammation which converts into
a diffuse inflammation which may have different components, one which is the
cells from the periphery which have entered the brain and the other might be
the microglia, the resident macrophages of the brain, that have become activated.
Now not only inflammation is likely to spread but also the tissue damage.
So in the green spots again are areas where the lesions are formed.
Where you have focal tissue injury. Some of these lesions may recover by
remyelination, this is the process where new myelin sheaths are
formed again. However, in some of the lesions the damage may persist.
Now because the cells in the brain are highly connected and they depend on each
other, the damage to the myelin sheath may lead to secondary axonal
damage, this again might affect other neurons and spread within the
brain. So then, at the end you have a focal tissue injury which
have become more diffuse and widespread. Now the brain is
at risk for spreading of diseases because the cells are highly connected,
and the cells depend on each other. So all the dendrocytes depend on
neurons, and the neurons depend on the oligodendrocytes.
Now if this is really proven -- it's not known, this is just the hypothesis
for how the focal disease can be converted to a global disease. Now is
remyelination failing in MS? Now this is a brain here, stained in blue is myelin
sheath, and with light arrows you see chronically demyelinated plaques
in white, so most of the plaques in fact are not remyelinated. But with
red arrows, you see two plaques where remyelination was successful and
you can see this light blue staining which indicates local plaques
where remyelination has taken place. So if you quantify this
over different many patients and brains, then the number is around that
20% of the lesions can recover and remyelinate, while 80% fail to do
so. So indeed, there is a failure of remyelination, at least in great parts.
Now, this failure of remyelination could contribute to the spread of
axonal damage. So I will start now by giving you a bit of background about
myelination. So about oligodendrocytes and about myelin sheath
function and structure, the development of myelin, before discussing
how myelin supports axons. And then talking about remyelination in MS.
This is the first drawing of an oligodendrocyte by Hortega. And you can
see in this drawing the cell body and then these many, many different
fine processes. So each of these fine processes ends up in a
myelin sheath. And around 50 or so myelin sheaths are formed by one
oligodendrocyte in a human brain. So damage to one of these cells has
of course big consequences, because you lose many different myelin
sheaths on different axons. This is how myelin looks in an
electron microscopy image. So you can see in a cross section this
different layers are very tightly connected, there's almost no
cytoplasm in between. And only at the edges of the myelin segments,
the myelin loses this compound structure, parallel loops are formed and
both are tightly attached to the axons. These areas in between the myelin
segments are called nodes of ranvier. They are shown here, so these are
where the sodium channels are clustered, where action potentials are
generated. And this action potential jumps from one node to the other.
And this is the base of saltatory nerve conduction, which speeds up
nerve transmission by a factor of 100, compared to unmyelinated
axons. It also saves energy because the neuron doesn't need to
make the action potential, only at the nodes of ranvier.
A second important function of myelin as has been established by
Klaus Nave and Jeff Rothstein is the metabolic support of axons.
So the oligodendrocyte produces glycolytic products like lactate
and pyruvate, and these products can then diffuse through the
oligodendrocyte, through the myelin sheath, into the axon.
So, to say that oligodendrocytes fuel the axons with energy products.
Another important function is the modulation of neuronal networks by myelin.
So there is evidence that some tasks that have been learned associate with
forming new myelin sheath. For example, shown by MRI studies, piano playing
can lead to changes in the white matter and possibly correlate
with myelin sheath. So myelin is also important to change the behavior
to function of neuronal networks. I will now talk about how myelin is formed.
I will start with normal development before going to MS. So you see here
in these pictures, blue is the myelin stain and you can see how it starts in one area
and then spreads within the brain. So the most intense phase of
producing myelin is in the first year of the human, and then it goes on for
several more years until large areas of the brain have been filled with myelin. Later
stages would be the front part, which is the frontal cortex, the more
complex areas are myelinated the latest. So myelination is a multistep
process, and I will divide this into four different parts. So the first part is the
specification of oligodendrocyte precursor cells. This is now a spinal cord
cross section of a mouse, and the blue areas are the areas where OPCs are
born, are specified. And they distribute within the spinal cord and the red area is
the second wave of OPCs that are formed in a more dorsal area.
That also distribute within the spinal area. The same principle holds true for the brain,
where you have different centers where OPCs are specified and
distributed within the brain. This is how it looks like in the brain,
so in white you have the OPCs, they are born in these areas close
to the ventricles. And these cells then migrate into the brain,
they proliferate, and they settle in the evenly spaced distance
to each other. At the end there's a dense network of OPCs that are
kept into adulthood. Now the third phase is the differentiation of some of these
precursors cells. This occurs in different steps, so first you have the
precursor cell, then the pre-myelinating cell that we still have difficulty
to recognize, but then a mature myelinating oligodendrocyte. And there are many
factors that can regulate this differentiation process. I will not go into details,
just mention that they're intrinsic and extrinsic factors. So the intrinsic
factors are transcription factors that need to be turned on in a different
manner, and extrinsic factors come from the environment, from other
cells. For example, Wnt signaling needs to be turned off or electric
activity of axons promotes the differentiation process. The last
process is the generation of the myelin sheath. So when the cells
have differentiated, they send out the process. And this process
has to recognize now the axons to be myelinated, the recognition
process molecules have not been identified so far. Once their
recognition attachment is established, then this membrane
moves around the axon in a particular way. How it moves around, I will
show in this video. So in green you have the axon, in the left
corner you have an oligodendrocyte that will send out the process.
And you see how this process now attaches to the axon, and wraps
around it and then at the same time, there's an extension through the layers
inside. So the inner layer is the one that actually moves around
the axon. Now in multiple sclerosis lesion, these different steps
are recapitulated, or some of these steps. So you see in acute lesion
here, myelin has been removed, you only see the axons in green now.
And the oligodendrocyte precursor cells are now recruited into the
lesion, which signals exactly as during development, it's not completely
known. But probably also signals from microglia and macrophages
will contribute. Once they have settled in the lesion, the second step is the
differentiation of these cells. So they will now become more complex
and send out different processes that will attach to the axons
and wrap the membrane around the axon. Now not all lesions
are successful in remyelinating. And in fact, the minority only.
The majority of lesions look like this. Where you have the lesion, myelin has been removed,
you have some oligodendrocyte precursor cells in the surrounding of the
lesion, they have not made it into the lesion, instead you have
now astrocytes that have formed a scar. There is also extracellular
matrix components which have been deposited within the lesion.
Now it would be important within individual patients to see which
lesions can remyelinate and which lesions remain as chronic
lesions which are unable to remyelinate. So MRI would be the ideal
measurements, but unfortunately, there's not a specific sequence where we can
recognize myelin. But progress has been made with 7 Tesla MRI studies.
And I will show you a study performed by Daniel Reich, where they
looked at different patients and looked at these lesions for more than
one year. And looked at evolution of the lesions. For simplicity,
I will show you cartoons of this and not the actual MRIs.
So the upper row, which you see in red, is the immune cells that
have formed in this acute lesion. Now some of these immune cells
will resolve and there will be a rim that can be seen in MRIs,
a paramagnetic rim of immune cells at the edges. Now if this rim
persists and it correlates with poor recovery, so with no remyelination.
So this was shown in an autopsy where one of these lesions was
basically analyzed. And you can see in blue the myelin stain again,
and you can see the completely demyelinated lesion, and at the edges
is this inflammatory rim. And if you focus into these cells, you see macrophages
loaded with iron. So this is an indication of poor recovery of a
lesion. Not all lesions develop like this, so there were also lesions which were
able to recover by MRI criteria. Again, red is the inflammation, and you see this
paramagnetic ring, but now this ring does not persist. The transient
ring. And this correlates with better recovery. If you now plot these different
types of lesions for different patients, then an interesting pattern emerges.
So the young patients, or those with a transient paramagnetic rim,
so have good recovery, and the older patients are those which have
poor recovery. Now why does remyelination fail in MS?
So one hypothesis in the field is that there is a differentiation block
in the lesion. So OPCs are somehow recruited to the edges of the lesion,
but signals are missing that would instruct the cells to differentiate
into myelinating oligodendrocytes. So efforts have been made to
identify compounds that can promote differentiation of T-cells, and different
high throughput screens have been performed, and some of these
drugs are now entering first clinical trials. In hope, of course, that
we will have some remyelination therapies in the future.
So why is remyelination important? I mentioned that remyelination
is probably important to preserve the axon in the long run.
So the structure of the axon, but also to provide the axon
with metabolites for structure and support. Not only loss of
myelin could be a problem, but also myelin dysfunction. So here you have a
myelinated sheath, and if you focus into this myelin sheath, there are
areas where there is some cytoplasm. And these cytoplasmic areas are
important for the metabolism of the myelin sheath and also to get
metabolites across the myelin sheath to the axon probably. And we
know that this function of the cytoplasmic channel is associated with
late onset axon degeneration. If this occurs in MS is unknown, but
this is a second possibility that myelin dysfunction can also lead
to axonal damage. At the end I want to summarize the main points,
so in MS, progressive MS, there is a focal pathology which has been
spread to a more global pathology. We know that remyelination
is insufficient in MS, so most lesions are in fact not remyelinated.
Remyelination is a process that recapitulates many of the steps
that occur in development, and remyelination is important
probably to preserve the long term survival of the axons.
And I will end here, thank you very much for your attention.