Emerging Cellular and Molecular Strategies for Enhancing Central Nervous System (CNS) Remyelination.
brain
sciences
Review
Emerging Cellular and Molecular Strategies for
Enhancing Central Nervous System
(CNS) Remyelination
Mohammad Abu-Rub 1 ID and Robert H. Miller 2, * ID
1
2
*
Department of Neurology, George Washington University School of Medicine and Health Sciences,
Washington, DC 20037, USA;
Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and
Health Sciences, Washington, DC 20037, USA
Correspondence: ; Tel.: +1-202-994-6988
Received: 9 May 2018; Accepted: 13 June 2018; Published: 15 June 2018
Abstract: Myelination is critical for the normal functioning of the central nervous system (CNS)
in vertebrates. Conditions in which the development of myelin is perturbed result in severely
compromised individuals often with shorter lifespans, while loss of myelin in the adult results in a
variety of functional deficits. Although some form of spontaneous remyelination often takes place,
the repair process as a whole often fails. Several lines of evidence suggest it is feasible to develop
strategies that enhance the capacity of the CNS to undergo remyelination and potentially reverse
functional deficits. Such strategies include cellular therapies using either neural or mesenchymal stem
cells as well as molecular regulators of oligodendrocyte development and differentiation. Given the
prevalence of demyelinating diseases and their effects on the quality of life for affected individuals it
is imperative that effective therapies are developed. Here we discuss some of the new approaches to
CNS myelin repair that hold promise for reducing the burden of diseases characterized by myelin loss.
Keywords: demyelination; remyelination; multiple sclerosis; OPCs; oligodendrocytes; MSCs
1. Introduction
There are many forms of demyelinating diseases in humans, and they are often typified by the
loss or dysfunction of oligodendrocytes [1]. Although myelin loss per se is associated with conduction
blocks along myelinated axons that often lead to clinical deficits, it is usually followed by some degree
of axonal dysfunction or loss associated with the accrual of functional disability [2]. Remyelination is a
regenerative process whereby myelin sheaths are restored, and although spontaneous remyelination is
a normal physiological response after most demyelinating conditions [3,4], there is evident heterogeneity
in the extent of remyelination, with an estimated 20–30% of people with multiple sclerosis (MS) showing
extensive remyelination [5]. The study of developmental myelination, pathologic demyelination, and
remyelination has been instrumental in setting the stage for this emerging field and is evidenced by
the amount of work being undertaken to develop remyelinating therapies. Despite having achieved
milestones at developing disease modifying therapies that halt the progression of diseases like MS,
there is a paucity of directed therapies to repair or regenerate myelin [6]. Therefore, there is a need
to understand mechanisms of remyelination and causes of remyelination failure to be able to better
design strategies for enhancing remyelination. Here, we discuss some of these potential strategies,
particularly in relation to myelin biology in health and disease.
Brain Sci. 2018, 8, 111; doi:10.3390/brainsci8060111
www.mdpi.com/journal/brainsci
Brain Sci. 2018, 8, 111
Sci. 2018,
8, xof
FOR
PEER REVIEW
2. WhatBrain
Is the
Role
Myelin
in the CNS?
2 of 19
2 of 18
2. What
Is the Role
of Myelin
the CNS?system (CNS) relies heavily on the precise temporal and
The
functioning
of the
centralinnervous
spatial connectivity
of
populations
of
and their
axonal
Central
this connectivity
The functioning of the central neurons
nervous system
(CNS)
relies processes.
heavily on the
precisetotemporal
and
is the ability
axons to rapidly
and effectively
convey
to their
targets,
spatialof
connectivity
of populations
of neurons and
theiraction
axonal potentials
processes. Central
to postsynaptic
this connectivity
is the
ability
of axonsistodependent
rapidly and effectively
convey
potentials to
their postsynaptic
targets,
which in
most
instances
on their level
ofaction
myelination.
Myelin
is composed
of wraps
which
in most instances
dependent onthat
theiract
level
myelination.
composed of
or
or stacks
of modified
plasmais membrane
to ofinsulate
and Myelin
protectissegments
ofwraps
the axons
all
stacks
of
modified
plasma
membrane
that
act
to
insulate
and
protect
segments
of
the
axons
all
the
the while providing metabolic trophic support [7,8] (Figure 1). A primary function of myelin sheaths
while providing metabolic trophic support [7,8] (Figure 1). A primary function of myelin sheaths is
is to enhance the speed at which electrical impulses travel along axons and reduce the threshold
to enhance the speed at which electrical impulses travel along axons and reduce the threshold
required
for action
potential
propagation.
thediscontinuous
discontinuous
nature
of myelin,
required
for action
potential
propagation.This
This is
is reflected
reflected ininthe
nature
of myelin,
where there
a high
concentration
of of
sodium
theintervening
intervening
nodes
of Ranvier
[9].
whereis
there
is a high
concentration
sodiumion
ion channels
channels atatthe
nodes
of Ranvier
[9].
Not all Not
axons
in theinCNS
are myelinated,
but
aremyelinated
myelinated
tend
tolong
be long
projection
all axons
the CNS
are myelinated,
butthose
those that
that are
tend
to be
projection
axons
or in some
inhibitory
interneurons,where
where rapid
rapid flow
is important
and ifand if
axons or
in some
casescases
inhibitory
interneurons,
flowofofinformation
information
is important
such
axons
lose
their
myelin
sheaths,
their
ability
to
effectively
conduct
information
is
compromised.
such axons lose their myelin sheaths, their ability to effectively conduct information is compromised.
This slowing or even failure of axonal conduction can in turn result in disturbances of motor and
This slowing
or even failure of axonal conduction can in turn result in disturbances of motor and
sensory function as seen clearly in demyelinating neurodegenerative diseases such as MS. Short term
sensory function as seen clearly in demyelinating neurodegenerative diseases such as MS. Short term
loss of myelin often leads to axonal conduction blocks and temporary axonal dysfunction that is likely
loss of myelin
often
leads
to axonal[10];
conduction
andor
temporary
axonal
dysfunction
thatand
is likely
to recover
with
remyelination
however,blocks
long-term
chronic myelin
loss
without rapid
to recover
with
remyelination
[10];
however,
long-term
or
chronic
myelin
loss
without
rapid
effective remyelination can lead to axonal degeneration with ensuing persistent functional deficits and
effective[11].
remyelination can lead to axonal degeneration with ensuing persistent functional deficits [11].
Figure
1. Structure
the myelin
sheath
thecentral
central nervous
nervous system
(CNS).
(A)(A)
schematic
diagram
Figur (...truncated)
