"We've got a long ways to go, but we're optimistic that these findings could
make a difference in the lives of these patients."
Scientists for the first time have restored a crucial substance known as
myelin in a widespread area of an animal's brain, opening the door toward
new ways to improve treatment of an assortment of "demyelinating" diseases
as well as the side effects of such common conditions as high blood pressure
and heart disease. The research by a team led by Steven Goldman, M.D.,
Ph.D., of the University of Rochester Medical Center, is in the January
issue of Nature Medicine.
Using human brain cells, Goldman's team was able to restore proper nerve
function in nearly the entire brains of mice much more efficiently than has
been done previously. While the work is years away from a clinical study in
humans, it serves as a milestone for researchers seeking to use stem cells
and related cells known as progenitors to treat human disease.
"The results are much better than we expected," says Goldman, who is
professor of Neurology and chief of the department's Division of Cell and
Gene Therapy at Rochester. "The percentage of cells in this experiment that
began producing myelin is extraordinary, probably thousands of times as many
as in previous experiments."
The work has implications for a wide variety of children's diseases known as
pediatric leukodystrophies, where the myelin is damaged or doesn't work
correctly, such as Canavan disease, Krabbe disease, or Tay-Sachs disease.
"While these diseases are generally rare, there are a lot of them, and
together they affect thousands of children and their families," says
Goldman. "We've got a long ways to go, but we're optimistic that these
findings could make a difference in the lives of these patients."
The work focuses on myelin, the fatty substance that covers nearly all the
nerve cells in our bodies - like insulation wrapped around a wire - and
helps signals in the nervous system go from one point to another. When the
myelin breaks down, as in multiple sclerosis or the leukodystrophies,
electrical signals degrade. It's as if a crisp and clear phone conversation
between two people speaking on land lines suddenly becomes patchy, sporadic
and intermittent, as if they were speaking on cell phones in a hilly area.
The net result can be dementia, difficulty walking, trouble breathing - a
problem with any normal activity, depending on which parts of the brain or
nervous system are affected.
The team remyelinated the mice - restored the "insulation" to the brain
cells- by injecting into the mice highly purified human "progenitor" cells,
which ultimately evolve into the cells that make myelin. These cells are
known as oligodendrocytes: While these and other types of glial cells aren't
as well known as information-processing brain cells called neurons, they are
vital to the brain's health.
"Neurons get all the press, but glial cells are crucial to our health," says
The team studied 44 mice that were born without any myelin wrapped around
their brain cells. Within 24 hours of their birth, scientists injected cells
that become oligodendrocytes -myelin-producing cells - into one precisely
selected site in the mice.
Scientists found that the cells quickly migrated extensively throughout the
brain, then developed into oligodendrocytes that produced myelin which
coated or "ensheathed" the axons of cells in the brain.
"These cells infiltrate exactly those regions of the brain where one would
normally expect oligodendrocytes to be present," says Goldman. "As they
spread, they begin creating myelin which wraps around and ensheaths the
Goldman says that while scientists have used other methods during the past
two decades to remyelinate neurons in small portions of the brains of mice,
the remyelination seen in the Nature Medicine paper is much more extensive.
He estimates that about 10 percent of the axons in the mouse brains were
remyelinated, compared to a tiny fraction of 1 percent in previous studies.
Currently, demyelinating diseases are permanent, and problems worsen as time
goes on because there is no way to fix the underlying problem - restoring
the myelin around the axons of brain cells. Goldman is hopeful that infusion
of cells like oligodendrocyte progenitors might be used to offer relief to
"The implantation of oligodendrocyte progenitors could someday be a
treatment strategy for these diseases," says Goldman, a neurologist whose
research was supported by the National Multiple Sclerosis Society and the
National Institute of Neurological Disorders and Stroke. While the
experiment provides hope for patients, Goldman says that further studies are
necessary before considering a test in humans. Currently he's conducting
experiments in an attempt to remyelinate not just the brains but the entire
nervous system of mice.
In addition to MS, many diseases affecting tens of millions of people in the
United States involve myelin problems, Goldman says. These include
widespread diseases like diabetes, heart disease and high blood pressure,
where decreased blood flow can damage myelin and hurt brain cells, as well
as strokes, which often destroy brain cells in part by knocking out the
cells that pump out myelin. In addition, cerebral palsy is largely caused by
a myelin problem in infants born prematurely.
The team found that adult human cells were much more adept at settling into
the brain, becoming oligodendrocytes and producing myelin than the fetal
cells. After just four weeks, adult cells but not fetal cells were producing
myelin. After 12 weeks, four times as many oligodendrocytes derived from
adult cells were producing myelin - 40 percent, compared to 10 percent of
the cells from fetal cells. In addition, adult cells were likely to take
root and form oligodendrocytes, not other brain cells such as neurons or
astrocytes, which are not necessary for myelin production. On average, each
oligodendrocyte from an adult cell successfully remyelinated five axons,
compared to just one axon for fetal cells.
"The adult-acquired cells not only myelinate much more quickly, but more
extensively - they myelinate many more axons per cell, and they do so with
much higher efficiency. The adult cells were far more efficient than fetal
cells at getting the job done," Goldman says.
An expert on the brain's stem and progenitor cells, Goldman in 1999 isolated
the cell that produces the oligodendrocyte, becoming the first person to
isolate a progenitor cell in the brain (both stem cells and progenitor cells
can develop into different types of cells, but unlike stem cells,
progenitors cannot renew themselves indefinitely.). Later his team
discovered that the cell is "multi-potential" - it can evolve into an
oligodendrocyte, a neuron, or an astrocyte, depending on the timing and
environment of a particular section of the brain.
Besides Goldman, other authors of the Nature Medicine paper include Martha
Windrem, Ph.D., of the University of Rochester; Marta Nunes, William
Rashbaum, Theodore Schwartz, and Neeta Roy of Cornell; and Robert Goodman
and Guy McKhann II of Columbia University Medical School.
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585-275-1200Submitted 1/19/2004 10:17:21 PM