A team led by Steven Goldman, M.D., Ph.D., of the University of Rochester Medical Center has injected both embryonic and adult stem cells into mice that were previously genetically engineered to be deficient in the insulation covering nerve cells that is called myelin sheath. The injected stem cells restored some of the missing myelin sheath.
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 Goldman.
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 axons.”
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.
If the auto-immune attack on the myelin could be stopped in Multiple Sclerosis (MS) suffers then even a repair of 10% of the damage would improve functionality. That might be enough of a difference to allow someone in a wheelchair to walk with the assistance of a walker or it might be enough to allow a person to feed himself.
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 patients.
“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.
While it is widely known that Multiple Sclerosis (MS) is caused by an auto-immune attack that eats away at the myelin sheath Goldman points out that many other diseaes involve myelin damage. Therefore myelin restoration would help repair damage associated with many disease which become more common as we age.
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.
Given that myelin, like everything else, deteriorates with age the ability to even partially repair it with a stem cell therapy would even offer some prospects for improving cognitive function in the aged.
Nervous system repair is an especially important and especially difficult rejuvenation challenge. Eventually it will be possible to grow replacements for most organs. But the brain must be repaired in place and in ways that do not cause any damage to existing networks of nerves. Therapies that hold the prospect of repairing even a limited subset of all nervous system age-related damage are cause for excitement.
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.
The adult-acquired cells (a.k.a. adult stem cells) have a big advantage: they are already more specialized for the desired task. The biggest advantage of embryonic stem cells is also their biggest disadvantage: they can become any kind of cell. Well, to develop a stem cell therapy for a particular disease one usually has to make stem cells become more specialized to produce only one or a few final functional cell types (what biologists call differentiated cells). Embryonic stem cells delivered into a diseased organ that needs a particular cell type may turn themselves into a number of different cell types and many of the cell types the embryonic cells will become are cell types that are not going to help in treating the disease that is being targetted for therapy.
This is not to say that adult stem cells are ideal in all respects. First of all, one needs to find a type of adult stem cell that is capable of becoming the target differentiated cell type that is needed. We do not know adult stem cell types for each final differentiated type and some adult stem cell types are hard to isolate. Plus, adult stem cells from adults frequently act like they are older. They grow more slowly. In fact, the aging of stem cells in adult stem cell reservoirs is a major contriibutor to general aging and we need the ability to replenish adult stem cell reservoirs with younger adult stem cells. For instance, it may be possible to avoid or delay atherosclerosis and heart disease by rejuvenating adult stem cell reservoirs. Whether this is best done by taking adult stem cells and rejuvenating them or by taking embryonic stem cells and turning them into adult stem cells remains to be seen. But one advantage of rejuvenation of one's own adult stem cells is that this would avoid auto-immune problems from use of embryonic stem cells that are not from one's own tissue.
The classic leukodystrophies include adrenoleukodystrophy, Krabbe's globoid cell, and metachromatic leukodystrophy, and a few other less well known entities. They have in common a genetic origin and involve the peripheral nerves as well as the central nervous system. Each is caused by a specific inherited biochemical defect in the metabolism of myelin proteolipids that results in abnormal accumulation of a metabolite in brain tissue. Progressive visual failure, mental deterioration, and spastic paralysis develop early in life, however, variants of these diseases have a more delayed onset and a less progressive course. The other primary white matter disorders include Alexander's disease, Canavan disease, Cockayne's syndrome, and Pelizaeus-Merzbacher's disease
When babies are born, many of their nerves lack mature myelin sheaths, so their movements are gross, jerky, and uncoordinated. The normal development of myelin sheaths is impaired in children born with certain inherited diseases, such as Tay-Sachs disease, Niemann-Pick disease, Gaucher's disease, and Hurler's syndrome. Such abnormal development can result in permanent, often extensive, neurologic defects.
|Share |||Randall Parker, 2004 January 20 01:27 PM Biotech Organ Replacement|