January 20, 2004
Stem Cell Therapy Replaces Missing Myelin In Mouse Brains

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.

There are many genetically caused myelin diseases.

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

Tay-Sachs disease is among the genetically based myelin diseases.

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


Comments
Fly said at January 20, 2004 7:27 PM:

What would happen if an old mouse were given an injection of embryonic stem cells everyday? Seems an obvious thing to try but I’ve never read of it being done. Google give lots of mouse stem cell info but nothing on this. (I have read that rebuilding the thymus by injections of thymus stem cells seems to rejuvenate an old mouse’s immune system.)

This experiment with brain progenitor cells might explain why I’ve read nothing on the above mouse experiment. Most of the injected embryonic stem cells die. Embryonic stem cells might not differentiate, migrate to the right tissue and take up proper function. Maybe proper organ preparation followed by infusion of the appropriately differentiated embryonic stem cells would rejuvenate an organ. (Assuming that aging is largely due to exhausting the body stem cell reservoirs.)

Another question is where are all the body stem cell reservoirs (e.g. bone marrow) and what controls when a stem cell migrates from one location to another. Perhaps rejuvenating the stem cell reservoirs would produce more progenitor cells.

Randall Parker said at January 20, 2004 8:37 PM:

Fly,

Stem cell reservoirs: they are all over the body. For instance, along the surfaces of muscles there are progenitor cells for making new muscle cells. It is likely there are many more types of progenitor cells or stem cells in an adult body than have been discovered to date. Periodically some new class of stem cell is discovered.

Stem cell migration control: Lots of things control it and it depends on the purpose of the stem cells. Inflammation signals are one way stem cells are attracted to a target. But that is mainly for injury repair. Not all stem cells are used to repair injuries. For instance, hippocampal stem cells differentiate to form new nerve. Most of the time that probably is not done in response to injury signals.

Ros said at March 14, 2004 2:39 AM:

My son's paediatric neurologist explained that my son's loss of myelin is in fact the result of neuronal loss which occurred during the period of asphyxia he suffered at birth. If I understood him correctly, myelin doesn't exist for its own sake but rather as a partner of neurons, conducting their messages to desired destinations. Thus, the 'marked loss of white matter' seen on my son's MRI implies 'marked neuronal loss' as well. Hence, if we are to try to build new myelin via adult or foetal stem cells, don't we need to build the lost neurons at the same time or perhaps first? Otherwise the olygodentricytes would have no anchor, so to speak.

mojgan said at March 30, 2004 4:18 AM:

To who to be concern,
My son is 5 years old. He had an intra ventricular hemorrhage after birth.
He is a CP child now .I heard something about stem cell transplants and repair brain for CP children.
Is it correct? Do I hope about threat my child?
Can you give me some information about that?
Thank you so much
I ‘m waiting to hear you
Mojgan
Mojgan_jalili@yahoo.com

Rachel said at May 25, 2004 4:23 AM:

my Son has a myelin sheath migration disorder and is in a wheelchair because of it. he is a bright child and it does not affect his thinking it does affect his eating talking and mainly the left side of his body. is there any place trying thigs like this on humans yet?

Rachel

Milaire said at October 1, 2004 6:20 AM:

I have two diseases, one is a neurological muscle disorder call "Scoliosis" In my case my spinal cord is spiraled at approximately 40% from my pelvis to my brain stem. The other is a rare disease call "Tremors" according to my Neurologist. He says I over produce adrenalin and thats why I get shaking convulsions, I short circut and cannot cordinate physical and mental functions well during even minor events. Is it possible my myelin is has been lost over the years. When it happens, I feel my working muscles in my back quiver. It's like their not in control and they are irraticle, they do not quiver at the same time. Obviously a communication failure is happening within me. Could it be a myelin problem?

When severe attacks happen I cannot breath well and loose oxygen and that causes heart failure.

The doctors I've seen say I will get worse. Is there no prventative or constructive medicine to improve my myelin within my body system. Does anyone know?

I'm a 46 year old male if that makes a difference.

Did I burn out my circut from over work and stress as I pushed my body physically? If we know the answer to that then others may prevent the samething to happen to them.

I built my horse farm and use to ride horses, love to dance and this year I feel like my body is killing itself.

So far the only way I have found it possible the be physical and not to go into convulsions is to take large doses of clonasepam, robaxeset and plenty of alcohol.
I still feel the convusions coming(before it's to late), so I stop sit and wait five to ten minutes and resume the physical activity.

This seems constructive and destructive at the same time. One doctor says to keep it up as my body functions better two days latter - the prior days I'm completely wasted.

Does anyone have any answers?

Nur said at March 6, 2005 1:43 PM:

HI,
My son is two years old and has been diagnosed Peho Syndrome(Progressive Encephalopathy,Edema with Hipps Arrythmy and Ophthalmic Atrophy) when he was five months old.In this disease myelinisation of nerves cannot be accomplished.I wonder if he has a chance of stem cell therapy.

Alma said at November 28, 2005 12:54 PM:

Child is now 3 yrs old and has grand mal seisures. At the age of 1 she received the mmr vacination and one week after she had a seizure, since then her developmental growth has seized. Every doctor that has seen her states that the vacination had nothing to do with her seizure. First Seizure lasted about 6-7 hours and the every test possible was made on her..all came back negative. Before her first seizure on May 15, 2002 she was reaching her developmental goals, crawling, standing (not walking) but moving from side to side, babling. since then she was had several more seizures and does not walk or talks she has high tone through out her body. she does not have cp and her doctors have not labeled her they found that she has had neurological disorder. she is currently taking 1cc of kepra, 75 mg phenobarb, 2.25 baclofen. Doctor plans on weinning her off if she does not have any more seizures we are hoping for february 2006. I have taken her to see a doctor in san diego (cranial therepy) and have taken her off some dairy product, which has helped a little she seem for focus and alert. She is doing but better hear of stem cell therapy and hope to find some answers.

lavonna said at January 31, 2006 1:14 PM:

try the child on real grape juice and real corn syrup in pure water for a few days to see if this helps the brain to get energy and stinulation to stop seizures I donot know how she survied seizer for all those hours she must have a strong sounds like she has a digestion problen that does not absorb the sugar to the brain I know from 64 years of not digesting enought carbs to brain that produce sugar to function

Tommy N. Dubone Sr. said at May 2, 2006 12:42 PM:

Approximately 3 1/2 years age, I severly twisted my ankle. When the pain left, the limp did not leave. The limp got worse over time and I finally went to a doctor. After several doctors I ended up with a Nerologist. He gave me an extensive electrical and conductivity test and told me that my white blood cells were eating the mylein off of my peripheral nerves. At this time I have no control of my right foot and my right leg and knee are very weak. My balance is very bad and I need a cane to walk. Now i feel weakness in my left leg and knee. I now know that the term for what I have is demyelination of the mylelin within the peripheral nervous system. I have search everywhere for a cure and have found none. I would like to try a natural way to regrow the myelin on my nerves. Does any one know how to do that? Tommy N. Dubone

Alison Crepnjak said at December 20, 2006 11:15 PM:

I am an athletic 42 year old female with double 70 degree idiopathic scoliosis. I have been postponing surgery in the hopes of a new and better procedure. Todays procedure would fuse me from T2 to L4. I am hoping for a non-invasive and aesthetically pleasing procedure. Currently, I am controling the pain through acupuncture, competitive swimming, running, weight training, stretching, and daily naps. I have had to reduce the amount of chores I do in a day around the house, and I can no longer do my gardening without experiencing great pain; therefore, I usually avoid any kind of gardening. Are there any biochemists, labs, or doctors who are working on stem cell therapy for scoliosis. I am aware of a Dr. David Bradford in San Francisco who was an orthopaedic scoliosis doctor who now does work on stem cells and back pain patients. I tried to contact him a few times, but have not heard back. Can anyone be of assistance? Any information would be much appreciated. Thank you.

Alison Crepnjak

suma. said at March 24, 2007 3:15 AM:

My daughter is ten year old, suffered birth asphyxia. she gets focal seizures which are infection related. Her milestones are delayed in regard to speech, mobility and learning. she is undergoing physiotherapy and occupational therapy. she is on anticonvulsant medicines,the dosages are
syrup Epilex- 10ml tds
tabletTopomac- 100mg bd

I would like to know whether stem cell transplant will help my daughter overcome the problem of seizures and catch up the milestones. can you give information on that? Any information would be appreciated. Thank you.

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