Regenerating Nerves 15-20 Times Faster!

[Christopher]

Great science at work!

One major problem for folks, like us, with Brachial Plexus Injuries is that nerves can never regenerate fast enough to extremities such as hands before the muscles atrophy beyond return. Axon regeneration speed would be another huge obstacle once re-implanting nerves back into the spinal becomes possible. Nerves regenerate at a rate of about an inch a month, so for someone like me, with 37 inches from neck to finger tip, it would take about 3 years for axons to reach final target muscles, by then they are useless.

This article proves, again, the need for Embryonic Stem Cell Funding and support from our government!

-Chris

----------------------------
http://www.eurekalert.org/pub_releases/ ... 110306.php

Public release date: 3-Nov-2006


Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital


Growth factor stimulates rapid extension of key motor neurons in brain

MGH study first to identify factors controlling growth of brain cells damaged in ALS

A growth factor known to be important for the survival of many types of cells stimulates rapid extension of corticospinal motor neurons – critical brain cells that connect the cerebral cortex with the spinal cord and that die in motor neuron diseases like amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). In the November 2006 issue of Nature Neuroscience, two investigators from Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute describe how insulin-like growth factor 1 (IGF-1) dramatically increases the in vitro growth of corticospinal motor neuron (CSMN) axons – projections that carry nerve impulses to the spinal motor neurons that connect to muscles – and that blocking IGF-1 activity reduces that growth in both cultured cells and in living mice.

"Our findings that IGF-1 specifically enhances both the speed and extent of axon outgrowth of corticospinal motor neurons are the first direct evidence of growth factor control over the differentiation of these neurons, " says Jeffrey Macklis MD, DHST, director of the MGH-Harvard Medical School (HMS) Center for Nervous System Repair, the report's senior author. "In addition to providing insight into the development and circuit formation of this critical population of neurons, these results might lead to the future ability to treat motor neuron disorders and spinal cord injuries."

Although their cell bodies are located in the brain, CSMN axons extend down to the neurons they control in the spinal cord – extending as far as three feet in adult humans. These neurons degenerate in ALS and related disorders, and their damage contributes to loss of motor function in spinal cord injuries. Since they are embedded among hundreds of other types of neurons in the cerebral cortex, it has been difficult to study CSMN, and little has been known about cellular and molecular factors that control their growth and development. In order to study growth factor controls over these cells, Macklis and Hande Ozdinler, PhD, a postdoctoral fellow in his laboratory, developed a new way of isolating pure populations of CSMN in culture and found that IGF-1 was a prime candidate for control over CSMN development.

Using these purified neurons, they then showed that two ways of applying IGF-1 – generally adding it to culture dishes or placing IGF-1-coated microbeads right next to CSMN cell bodies – both increased the growth of axons by 15- to 20-fold, reaching the very fast rates previously seen only during initial development. Blocking the interaction between IGF-1 and its receptor reduced axon growth to control levels, confirming that the IGF-1 pathway is critical to the enhancement effect.

Experiments with another type of neuron and with several different growth factors verified that axonal growth was stimulated only by IGF-1 and only in CSMN. The researchers also showed that IGF-1 enhancement of axonal growth operates separately from the growth factor's known support of neuronal survival. Tests in living developing mice showed that blocking the IGF-1 pathway in the spinal cord prevented the growth of CSMN axons, which confirmed the applicability of the in vitro experiments to living mammals.

"The role of IGF-1 as a potent and specific enhancer of CSMN axon growth is highly relevant to our understanding of this critical population of neurons. These findings are a first step that may someday lead to ways of treating the neuronal degeneration of diseases like ALS, regenerating cells for the treatment of spinal cord injury, and to the potential replacement of neurons using precursors or 'neural stem cells'," says Macklis, who is on the faculty at Harvard Medical School.

###
The study was supported by grants from the National Institutes of Health, the ALS Association, and the Harvard Center for Neurodegeneration and Repair.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare System, a Boston-based integrated health care delivery system.

[kaz]

Thanks Chris. I always find your articles interesting.
When I hunt on the web for info about my new "club"
9 outa 10 x I've already read the article from you!

[fortitudine]

Is this similar to the work being done by Dr. Carlstedt?

[Christopher]

No, completely different.

Carlstedt is mainly a neurosurgeon, and does research on the mechanics of trying to reattach nerves back into the spinal cord. The clinical trials for nerve re-implantation (that were supposed to begin in February of this year, then again in September, but haven't started yet) taking place in the UK are with Dr. Carlstedt, but again he is the surgeon, the researcher that is using stem cell derived Olfactory Ensheathing Glial cells is Professor Geoffrey Raisman. I'm sure they would both be very interested in this research, as it would further both of their work.

[Kath]

Here is another research paper on stem cell regeneration

http://www.npr.org/templates/story/stor ... Id=5696557

[Christopher]

Here's a recent publication from Harvard University on this encouraging work...


~Chris


------------------------------
http://www.news.harvard.edu/gazette/200 ... erves.html


Published:
November 9, 2006


Growth of spinal nerves is improved

Could play a role in spinal cord repair

William J. Cromie
Harvard News Office

Nerves that control the highest level of voluntary movements have been isolated and secrets of their growth revealed for the first time.

During development, these nerves extend themselves from the brain to all levels of the spine with the help of a potent growth factor called IGF-1. This factor is well known to scientists. However, the discovery of its role in guiding the extension of the longest nerves in the body was a big surprise.

The discovery has researchers talking about new ways to treat ALS, or Lou Gehrig's disease, and other paralyzing disorders, as well as regenerating spinal nerves that have been damaged by falls, crashes, and combat.

"Our experiments are highly relevant to understanding the basic development of the central nervous system of humans and other mammals," says Jeffrey Macklis, director of the Massachusetts General Hospital-Harvard Medical School Center for Nervous System Repair. "Learning how these nerves, known as corticospinal motor neurons (CSMN), establish connections between the brain and spinal cord could help find new treatments for ALS and other diseases caused by nerve degeneration. Such knowledge might also contribute to efforts to repair spinal-cord injuries." These goals, still many years away, might be accomplished by regrowing damaged nerves or recruiting new nerves from adult stem cells.

Macklis and postdoctoral fellow Hande Ozdinler isolated the long motor neurons from a tangle of look-alike nerve cells in the brains of mice. They kept the cells alive in laboratory dishes then bathed them in IGF-1. They also put tiny beads carrying the growth factor next to the nerves and made microscopic movies of what happened. "The results were immediate," Macklis recalls. "Within 30 seconds, we saw a dramatic outgrowth of the axons [nerve extensions]. IFG-1 increased their rate of growth a striking 15 to 20 fold."

Since these kinds of experiments cannot be done on humans, mice were used. "Mice mimic many aspects of human biology on molecular and genetic levels," Macklis points out. He sees the cells that survive but do not grow in lab dishes as mimicking motor neurons in adults. Reintroducing them to IGF-1 is like turning the biological clock back to infancy, when brain development is at its swiftest, and a baby is moving from uncoordinated flailing to drawing with crayons.

Reaching out

These experiments are part of an ongoing effort by Macklis and many others to determine how specific types of neurons form from unspecialized precursor or stem cells during the development of the human brain (see March 17, 2005, Gazette). "We want to dissect the brain one cell type at a time to uncover the many gears and cranks that make it work," he says.

The bodies of CSMN cells sit in the cerebral cortex, the largest most developed part of the brain. From there they send out long hairlike extensions called axons. In a fully formed human, an axon reaching down to the lower spine is as long as three feet. The brain uses these connections to communicate with the nerves that move fingers and legs in tasks like writing, sketching, and playing sports. When such connections are cut off in ALS and other diseases or because of injuries, the brain cannot make the body do what it wants to do.

Using techniques devised in their laboratory, Ozdinler and Macklis labeled target neurons from the spinal cord with fluorescent markers, then worked backward to the brain to sort and separate them into collections of pure CSMN cells that could be nurtured in laboratory dishes. They describe these efforts in the November issue of Nature Neuroscience.

Speeding up the messages

Once they uncovered the gears and cranks involved in tweaking CSMN growth, the researchers carefully disabled each one in mice. Things happened or didn't happen in the animals the same way as in the dishes. When IGF-1 was added to other types of nerves, no sudden or startling increase in axon growth was found. "This convinced us that we were seeing the 'real biology' of how these neurons connect the brain to the spinal cord," Macklis notes.

During development, CSMN axons reach out at the rate of about a half-inch in 10 days. After a week or two, the rate slows precipitously to approximately one inch in 25 weeks. In a developing baby, these nerves extend themselves from the brain to the spine in just a few weeks.

At the much slower rate of growth and with the longer distance to cover in adults, such extensions might require several years. "A neuron will not survive that long if its axon hasn't reached its target in the spinal cord," Macklis points out. "With the IGF-1 potential to increase growth rates 10 to 20 fold, one could imagine future treatments that may cut that time to months."

At this point, researchers can only imagine such a shortcut. There's too much to learn before it becomes a reality. For instance, what are the "seeing-eye" molecules that guide a nerve extension from the brain to the spinal cord? Some molecules that direct axon traffic are already known. They can attract or repel nerve endings or steer them left or right. However, the specific CSMN guides remain a mystery. "We are actively involved in looking for them," Macklis says with a note of urgency.

Once that kind of information becomes known, what happens in laboratory mice might be induced to happen in disabled humans.

Macklis, who is also head of the Nervous System Disease Program of the Harvard Stem Cell Institute, looks to recruiting new neurons from adult stem cells, present in small numbers in all adults. Using the right control molecules and growth factors, such cells might be coaxed into developing into new motor neurons that grow from the brain to the spinal cord. Another way to do this might be to take adult stem cells out of a patient, give the cells the character and growing ability they need, then transplant them back into the brain.

Macklis, Ozdinler, and others believe that such goals can be reached in the future. Progress made so far convinces them the damage that takes away the ability of people to move the way they want to move can be repaired.