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Growth factors in the brain

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#1 henri

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Posted 03 September 2005 - 09:54 AM

It has been said that the neurons from embryos that one transplants into patients (in Parkinson's disease, for instance) don't form synapses with other neurons once they've been put in place. Still, the condition may improve. One explanation is that the newly transplanted neurons secrete GF:s (growth factors) that affect other neurons. I'm not sure if I'm bying this because it would seem strange that the GF:s would induce growth in the degenerated neurons that were in the brain originally while the new, healthy ones would be unable to respond. Or maybe the connections that already exist can be strengthened, but no new ones formed in the adult brain when the particular growth factors are applied.

Also, there have been studies in which GF:s have been introduced into the brain by more direct means and improvement may have resulted. I think that the lack of GF:s has been conceived to be one thing that causes age-related changes in the nervous system (in general, connections seem to get fewer in at least some parts of the brain).

If the aging brain isn't producing enough growth factors, why doesn't it? One way to explain this would be that the neurons are getting so weak that they can't. In this case, all one would need to do would be to apply rejuvenating treatments to the cells. But it might also be a more complicated issue, in which case the treatments would more complicated be as well. Maybe the GF system is rather independent from other age related changes. I guess one would just have to check it. But neurons can't survive very long on dishes, or can they? If they can't be made, it might be difficult to disentangle this process from the others.

#2 liorrh

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Posted 03 September 2005 - 01:18 PM

the big picture
the GF secretion is a result of activity. the beuronal bundles use GF to remodel themselves to better suit current activity.

so generaly if your brain is not active in a certain part, that part will not generate GF.

I think this is the main reason, others being concurrent drop in the efficiency of other systems, like immune and endocrine which regulate GF centrally.

#3 John Schloendorn

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Posted 03 September 2005 - 05:10 PM

It is often not just a matter of having growth factors and period. Sometimes they need to be secreted locally to create a so called microenvironment. Some people imagine this to be a complicated 3D-landscape of growth factor concentrations, with tiny gradients and all sorts of patterns down to the micron-scale to properly direct the growth of the complicated microstructures that make up our neuronal network. You could not get this right in all cases with an injection. It's generally something that only cells can do.

As for why does it stop working, this is less than clear. I think it's safe to say that there are both components of decreased growth factor production and growth factor resistance, each possibly ultimately due to age-related cell damage, but it is for the greatest part not known just how this looks like in detail.


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Posted 04 September 2005 - 03:00 AM

Excellent observation Henri - and most relevant for brain rejuvenation discussions where stem cells are to be used therapeutically.

Brain/neuron related growth factors, specifically brain derived growth factor (BDNF) and nerve growth factor (NGF) -- and there are many others functioning in either inducive or inhibitive fashion according to the receptor types present on the neuron -- are critical in determining the growth path that the axon of a developing neuron in the embryo takes from its point of origin to its synaptic target. They are also critical for the maintenance of neurons in the adult. Like many other growth factors, these decline drammatically after a certain age - but that is another matter.

Of importance is that in any stem cell type therapy irrespective of the amount of stem cells one can introduce in the brain, unless they are presented with the appropriate NGF, BDNF, etc type signals which create a 3-dimensional morphogenetic gradient as John has described which guide the axonal and dendritic projections of the neuron to synapse with the appropriate region, will merely lie in amorphous dormancy until - due to lack of growth factor - they apoptose. This is precisely the reason why stem cell transplantation in the brain - barring a short period of dopamine level increase in the case of Parkinson's disease patients - all ultimately fail. The transplanted neural stem cells are not receiving the necessary signals for them to survive and form synaptic connections. Researchers are attempting to recode these neural stem cells by exposing them to growth factors in culture prior to transplantation to induce them to become more developmentally mature so that they are not as "naive" and dependant on growth factors as younger stem cells but still they have no success.

The problem, in my view, is that irrespective of the maturity (the degree of recoding) of the neural stem cell it still requires certain cues to guide its axonal and dendritic projections to synapse at the right places whilst in vivo, that is, following transplantation. Such cues no longer exist in an adult brain which has switched its expression of growth factors from developmental to maintenance requirements. Therefore either specific regions in the brain have to be encouraged to alter their expression of growth factors or the cues that the neural stem cells are looking for have to be redefined. Doable (certainly not the realm of science fiction), but will require new levels of technology and understanding which we do not presently have.

And this is why, until this not inconsiderable hurdle is dealt with, SENS cannot move forward on stem cell type brain rejuvenation.

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