EMERGING RESEARCH FRONTS
Bruce D. Trapp talks with
ScienceWatch.com and answers a few questions about
this month's Emerging Research Front in the field of
Neuroscience & Behavior.
Article: Premyelinating oligodendrocytes in chronic
lesions of multiple sclerosis
Authors: Chang, A;Tourtellotte, WW;Rudick,
Journal: N ENGL J MED, 346 (3): 165-173 JAN 17 2002
Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, NC30,
9500 Euclid Ave, Cleveland, OH 44195 USA.
Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, NC30,
Cleveland, OH 44195 USA.
Cleveland Clin Fdn, Mellen Ctr Multiple Sclerosis,
Cleveland, OH 44195 USA.
(addresses may have been truncated.)
Why do you think your paper is highly
The paper is highly cited because it is of interest to developmental
neurobiologists and clinical multiple sclerosis researchers. From the basic
science perspective, there is considerable interest in how oligodendrocytes
are generated and what regulates their differentiation into myelin-forming
cells during development and following demyelination.
The best example of repair of the adult human brain is the generation of
new oligodendrocytes that remyelinate demyelinated axons in the lesions of
multiple sclerosis. Unfortunately, this repair process is not always
successful. Because the Multiple Sclerosis (MS) brain can endogenously
replace myelin, it is likely that the repair process can be therapeutically
manipulated and enhanced in those lesions where repair fails. Remyelination
requires generation of new oligodendrocytes from an oligodendrocyte
Our studies investigated whether oligodendrocyte progenitor cells,
production of new oligodendrocytes, or differentiation of oligodendrocytes
limits remyelination in chronic MS lesions. We demonstrate that the
replacement of oligodendrocytes in MS lesions recapitulates many of the
steps described in development. Specifically, we detected oligodendrocyte
progenitor cells and pre-myelinating oligodendrocytes in chronic
demyelinated MS lesions and show positive correlation between the
distributions of these two cell types.
These observations support the contention that neither oligodendrocyte
progenitor cells nor oligodendrocyte production necessarily limit the
remyelination process. The observation that has received the most attention
is the detection of the pre-myelinating oligodendrocytes. These cells
express myelin proteins and extend processes that follow individual axons,
but they fail to form myelin around these axons. Thus, in addition to
increased oligodendrocyte production, we identified enhancement of
oligodendrocyte differentiation as a therapeutic target for remyelinating
Because many of the demyelinated axons in chronic lesions appeared
dystrophic, failure of remyelination by pre-myelinating oligodendrocytes
may be due to the lack of appropriate signals from axons. It is well
established that axons regulate the myelination process and how this is
accomplished is a major interest of basic scientists. Thus, our data is
cited in the context of the need to better understand the molecular
mechanisms of this axonal regulation, which could lead to therapeutic
approaches to enhance repair of chronic MS lesions.
Our data is also of interest to the clinical MS researcher because it
impacts design of future clinical trials. Transplantation of
oligodendrocyte-producing cells is a major focus of pre-clinical research.
Much of this research appropriately focuses on the type and source of the
cells to be transplanted. Equally important is the transplant recipient and
Chronic MS lesions have advantages as transplant sites and were the target
for a Phase I trial testing the safety of Schwann cell transplantation. Our
paper, however, raises the possibility that chronic MS lesions may not be
an appropriate transplantation site. Chronic lesions may support production
of premyelinating oligodendrocytes from transplanted cells (as occurs
However, if the environment of chronic MS lesions does not provide the
appropriate signals for pre-myelinating oligodendrocytes to successfully
remyelinate axons, increasing oligodendrocyte numbers will not result in
remyelination, nor benefit the patient.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
As is often the case, new methodology and synthesis of knowledge led to new
information. From the methodological point of view, the challenge was to
apply techniques that we developed for basic science studies of myelination
in rodents to human tissue. The first challenge was to develop a rapid
autopsy protocol for MS brains.
The Cleveland Clinic has one of the largest clinical MS programs in the
world. In collaboration with Dr. Richard Rudick and other neurologists at
our Mellen Center for Multiple Sclerosis Treatment and Research, we
established a protocol to rapidly access MS brains. The success of this
program reflects the dedicated MS patients who prospectively signed-up to
participate in this endeavor.
Our post-mortem protocol includes an in-situ MRI. Half the brain
is processed for MRI-pathology correlations and half for morphological and
biochemical analysis. We have processed over 50 brains and spinal cords
with post-mortem intervals averaging around five hours. Thus, we have a
significant collection of well-fixed brains for our studies.
The next methodological challenge was to get our immunocytochemical
techniques to work on human tissue, which was not an easy task. We do not
utilize routine histological stains or paraffin embedded tissue. Our
approach is to use immunocytochemistry to decipher the three dimensional
relationship of cells in 30um-thick sections using confocal microscopy.
Because my laboratory collects and processes the tissue in the autopsy
suite, we can prospectively modify tissue collection to our needs. For
example, our antibodies that detect oligodendrocyte progenitor cells do not
work on tissue slices that have been fixed for extended periods of time. We
limited fixation of brain slices to two days for these studies. Dr. Ansi
Chang, the lead author of the paper, spent an enormous amount of time in
optimizing the staining protocols for human tissue.
Most new discoveries require a synthesis of knowledge. My long-standing
interest in the basic science of myelination was a big factor in design of
the hypothesis on which our paper was based. We set out to ask two basic
questions. First, do oligodendrocyte progenitor cells (OPCs) limit
remyelination in chronic MS lesions? We partly addressed this question in a
paper published in 1999, by detecting cells that expressed phenotypic
marker of OPCs.
Of course, this observation did not prove that these cells had the ability
to generate oligodendrocytes. However, detection of OPCs and
pre-myelinating oligodendrocytes in the same lesions established the
presence of functional OPC in chronic lesions and addressed the second
hypothesis by demonstrating that oligodendrocyte production does not always
limit remyelination of chronic lesions. The significantly new discovery was
the failure of premyelinating oligodendrocytes to form myelin.
Would you summarize the significance of your paper in
The significance of our finding is a positive one for the MS patient. The
damaged brain of multiple sclerosis patients never gives up trying to
repair itself. This is important and encouraging because we have identified
the stage of the repair process that is blocked. This provides targets for
the development of new therapeutics that will optimize MS brain repair.
How did you become involved in this research and were
any particular problems encountered along the way?
My entire research career has focused on the cellular and molecular biology
of myelination. My Ph.D. dissertation investigated the effects of essential
fatty acid deficiency on myelination. My Ph.D. advisor, Joseph Bernsohn,
had hypothesized that essential fatty acids may lower susceptibility to MS,
based upon to the high intake of raw fish (a source of essential fatty
acids) and low MS incidence in Japan.
While there was a theoretical focus on MS, my studies were restricted to
rodents. Following my Ph.D., I joined the laboratory of Dr. Henry deF.
Webster at NIH as a postdoctoral fellow where two major influences shaped
my career. First, Dr. Webster was interested in both diseases of myelin and
the basic sciences of myelination. I learned to extend basic science
observations to relevant questions of disease mechanisms. Second, Dr. Nancy
Sternberger was also a fellow in Dr. Webster’s laboratory and her
husband, Ludwig, was developing the peroxidase-anti-peroxidase method for
localizing antigens in tissue sections.
We had access to these reagents well before they became commercially
available. This catalyzed a shift in my research to proteins and
immunocytochemistry, a focus I maintain today. I purified several
peripheral nerve myelin proteins in the laboratory of Dr. Richard H.
Quarles at NIH, generated antibodies and investigated their expression
during myelination. I published my first papers on human disease, including
a description of Schwann cell remyelination of demyelinated axons in MS
spinal cord and several papers on the pathogenesis of human peripheral
Following my postdoctoral fellowship, I joined the Department of Neurology
at Johns Hopkins University. This was a tremendous environment. I had
outstanding mentorship from Drs. Jack Griffin, Guy McKhann, Richard
Johnson, and many others who reinforced my interest in applying basic
science observations to human disease mechanisms. I learned the importance
and value of collaborating with clinicians who understood the diseases and
who could help put my observations in the context of disease pathogenesis
and progression. It was there that I had my first exposure to rapid autopsy
protocols that were developed to investigate the pathogenesis of
HIV-related CNS diseases.
I became interested in MS pathogenesis and was fortunate enough to obtain
several postmortem MS brains. It was a very difficult decision to leave
this environment for the Cleveland Clinic in 1994, because I was generating
some exciting data regarding axonal degeneration in MS. Following my move
to Cleveland, I turned much of my clinical focus to MS and established the
rapid autopsy program.
As part of my basic science research program, we identified reliable
markers for oligodendrocyte progenitor cells and premyelinating
oligodendrocytes. It was an obvious extension to determine if these cells
limit remyelination in chronic MS lesions. While I do not recall any
particular problems encountered along the way, an obstacle to our research
of MS tissue is the lack of brains from patients during early stages of the
Many lesions in early stages of the disease remyelinate and it would be
informative to characterize the environments that promote successful
remyelination. For the bigger picture, however, this obstacle is good
because the neurologists have greatly improved the quality of life and
lifespan of MS patients. Since that’s what our research is really
about, we will have to find other ways to characterize environments that
Where do you see your research leading in the
We are looking for mechanisms that enhance myelin repair and limit
neurodegeneration in MS brains. Degeneration of chronically demyelinated
axons is a major cause of the continuous and irreversible neurological
disability that most MS patients eventually endure. Remyelination is the
best documented neuroprotective therapy. Transplantation of progenitor
cells and manipulation of the endogenous repair process represent viable
repair approaches and both should be pursued.
We have a special interest in small-molecule therapies that may be combined
with transplantation. We also need a better understanding of how myelin
keeps the axon happy and functional. If one could find a way to make the
demyelinated axon think it is myelinated we could avoid some of the
complication of transplant therapies and provide an effective mechanism for
delaying disease progression.
Do you foresee any social or political implications for
Social and political implications will increase the closer we get to a
transplantation therapy. The issue will be the source of the transplanted
cells. We are very interested in
stem cells in the adult brain. One possible source
for generating the adult CNS stem cells is human embryonic stem cells, a
topic with both social and political implications. Fetal human brain is
a proven source of oligodendrocyte progenitor cells and a political
issue in the state of Ohio, where state law forbids research on any
fetal tissue derived from elective procedures.
Bruce D. Trapp, Ph.D.
Department of Neurosciences
Lerner Research Institute
The Cleveland Clinic
Cleveland, OH, USA
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