Boston, MA-Scientists at Schepens Eye Research Institute have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. Their findings are published online this week in the Proceedings of the National Academy of Science (PNAS).
A previous paper by the same group found stem cells in many more parts of the brain than stem cells were previously know to exist. This suggests more parts of the brain are repairable via mechanisms already there if we can only find ways to get control of those mechanisms.
An earlier paper (published in the May issue of Stem Cells) by the same scientists laid the foundation for the PNAS study findings by demonstrating that neural stem cells exist in every part of the brain, but are mostly kept silent by chemical signals from support cells known as astrocytes.
"The findings from both papers should have a far-reaching impact," says principal investigator, Dr. Dong Feng Chen, who is an associate scientist at Schepens Eye Research Institute and an assistant professor of ophthalmology at Harvard Medical School. Chen believes that tapping the brainšs dormant, but intrinsic, ability to regenerate itself is the best hope for people suffering from brain-ravaging diseases such as Parkinsonšs or Alzheimeršs disease or traumatic brain or spinal cord injuries.
Until these studies, which were conducted in the adult brains of mice, scientists assumed that only two parts of the brain contained neural stem cells and could turn them on to regenerate brain tissue-- the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). The hippocampus is responsible for learning and memory, while the SVZ is a brain structure situated throughout the walls of lateral ventricles (part of the ventricular system in the brain) and is responsible for generating neurons reponsible for smell. So scientists believed that when neurons died in other areas of the brain, they were lost forever along with their functions.
Molecules named ephrin-A2 and ephrin-A3 inhibit neural stem cell growth. So inhibitors of those molecules might help to activate stem cells for brain repair. Sonic hedgehog (which the press release below misspells as sonic hedghoc) stimulates neural stem cell growth. Inhibit the ephrins and stimulate sonic hedgehog and the result would be much more neural stem cell growth.
In the second (PNAS) study, the team went on to discover the exact nature of those different chemical signals. They learned that in the areas where stem cells were sleeping, astrocytes were producing high levels of two related molecules--ephrin-A2 and ephrin-A3. They also found that removing these molecules (with a genetic tool) activated the sleeping stem cells.
The team also found that astrocytes in the hippocampus produce not only much lower levels of ephrin-A2 and ephrin-A3, but also release a protein named sonic hedghoc that, when added in culture or injected into the brain, stimulates neural stem cells to divide and become new neurons.
What I'd like to know: As the brain ages do the astrocyte support cells excrete more ephrin-A2 and ephrin-A3 and less sonic hedgehog? Maybe the aging brain becomes less able to do repair because evolutionary natural selection selected for stem cell inhibition as an anti-cancer strategy. Therapies to activate brain stem cells might increase risk of brain tumors. Of course, if you have Parkinson's Disease your trade-off might weigh to taking that risk as likely to deliver the best net benefit.
The eventual development of techniques to create youthful neural stem cells will provide stem cells that can be safely stimulate to grow without running a cancer risk. But How to replace the old stem cells with young ones? It is not enough to add the newer younger stem cells to the brain (and just getting the new stem cells into all the spots in the brain they need to go is a challenge). We need to get rid of the old stem cells so that a drug that boosts stem cell growth will only stimulate the new stem cells and not the old stem cells too.
I wrote a post back in November 2004 about the ability of sonic hedgehog to triple brain stem cell growth. The use of sonic hedgehog for this purpose is well known among the researchers in this area.
By Randall Parker at 2008 June 07 10:28 PM Brain Stem Cells | TrackBack"But How to replace the old stem cells with young ones? It is not enough to add the newer younger stem cells to the brain (and just getting the new stem cells into all the spots in the brain they need to go is a challenge). We need to get rid of the old stem cells so that a drug that boosts stem cell growth will only stimulate the new stem cells and not the old stem cells too."
Are the old stem cells really immobilized? If they operate like bone marrow stem cells then a fraction (a couple of hundred) leave the niches and circulate each day. Some of the circulating stems will again take up residence in other niches. Signaling molecules can increase stem cell mobility. By daily injections of several hundred young stem cells together with a stem cell mobilizing drug the old stem cells should be gradually replaced.
Capsules that act as stem cell niches and that release hundreds of stem cells each day could be implanted in strategic locations.
This is only a partial step for tissue regeneration. Old mouse muscle tissue is not rejuvenated when supplied young mouse blood. The signaling between young cells and old cells doesn't support healthy tissue repair. (On the other hand, old blood + young muscle tissue = healthy repair.) (For a discussion of Notch/Delta signaling see Futurepundit, http://www.futurepundit.com/archives/001834.html) Scientists will need to either kill the old cells or fix the signaling problem.
A similar problem exists in brain tissue. New neurons only survive if they make appropriate connections in the existing neural network. Too little or too much neural stimulation causes cell death. Scientists may need to locally adjust those "death" parameters to encourage new tissue growth. Also, for large injuries, restoring the proper wiring between brain regions could be difficult.)
(Another issue is cell fusion vs. cell replacement.)
Fly,
We have a big problem in that suppressor molecules probably circulate in our bodies as we get older and even if we replace stem cells or other cells in one area compounds in the blood might inhibit their division. We need to find out where those suppressor molecules come from and how many places in the body each kind of suppressor molecule acts on.
One trick we might be able to play is to add in new cells that ignore some of those suppressor molecules - at least for some number of years. But the overall suppressor molecules that increase in concentration as we age might also have more localized purposes. So programming cells to ignore them might introduce other problems.
For more on this problem of suppressor molecules preventing repair as we age see my posts Young Mice Blood Turns On Regenerative Ability Of Old Mice Muscle and also Wnt Suppresses Stem Cell Repair Work As We Age?. This build up of suppressor molecules seems very problematic for the development of rejuvenation therapies.
"We need to find out where those suppressor molecules come from and how many places in the body each kind of suppressor molecule acts on."
Yes. My terminology is local growth or signaling factors but essentially we are talking about the same thing. Replace old stem cells with young stem cells. Get the stem cells into the target tissues. Locally control the growth factors and signaling molecules (e.g., suppress the suppressors) so that the new cells repair damage and assume functional roles. In some tissues, slowly kill off the old cells. In other tissues, such as the brain tissue that holds long term memories, rejuvenation of old cells would be preferred with replacement by new cells only as necessary for retaining tissue function. Other non-memory brain tissues such as the retina could slowly be replaced by young cells. Special techniques might be needed to repair major nerve bundles. (Perhaps temporarily putting the tissue in an earlier developmental state. The person would temporarily lose function but the associated nerve fiber and neurons could rapidly be retrained after the new neurons had regrown the axon connections. Such technology will be needed to repair disease and injury even if rejuvenation wasn't the primary goal.)