Trophic Factors Generate Functioning New Neurons for Brain Repair

Research into using the brain's own 'hibernating' neural stem cells to repair brain damage advances in animal models.
One exciting area of research today is exploring the potential of neural stem cells. These "hibernating" cells in the brain have proved able to develop into new, functioning, adult brain cells ? and in the near future, they may go beyond, to be used in repairing brain injury caused by trauma and neurodegenerative diseases. One new set of studies raises hope that neural stem cells may be particularly valuable for Huntington?s disease.

In only the last decade, research has confirmed that the brain contains its own stem cells ? progenitor cells that can become adult cells of different highly specialized types. Stem cells in the brain, called neural stem cells, or NSCs, can produce both of the main kinds of cells in the brain, neurons and glia. (Roughly speaking, neurons are the main messaging cells of the brain, sending information long-distance by electrochemical impulses, while glia have a supporting role, in cleanup, immune, and other functions, which they carry out by coordinating with other brain cells locally.)

Neural stem cells, it turns out, are found throughout the brain, although neurogenesis, or the emergence of new neurons, generally takes place in just a few brain areas. Notable areas containing NSCs include the dentate gyrus of the hippocampus and the subventricular zone. Neurogenesis in these areas is believed to underlie important brain functions, including adaptation to the environment and memory.

NSCs are mutipotent (or pluripotent) rather than totipotent; that is, they can become several kinds of specialized adult cells, but only a few. (In contrast, embryonic stem cells can develop into any kind of cell in the body; they?re totipotent.)

Neural stem cells are found in tissue that lines the brain?s lateral ventricles, the hollow areas of the brain containing cerebral spinal fluid.

Usually, when these neural stem cells develop, they become glia. Glia are very common cells in the brain ? in fact, many times more common than neurons.

However, these same neural stem cells can become neurons instead, under the right conditions. Recent research shows they can be prompted to develop in significant part as new neurons, rather than glia, when exposed to the right growth or trophic factors. Trophic factors stimulate and guide growing neurons to their target locations, and help maintain new nerve cell connections.

Precursor neural cells grow in a lab dish, generating mature neurons (red) and glial cells (green) (Courtesy Su-Chun Zhang, University of Wisconsin-Madison).

Steven Goldman and his colleagues at Cornell University Medical College, Regeneron Pharmaceuticals, and the University of Rochester attempted to exploit these neural stem cells to achieve an innovative kind of brain repair (see abstract below). Using a technique known as viral gene therapy, they inserted the genes that produce two trophic factors, BDNF and noggin, into two different adenoviruses (viruses like the common cold). The adenoviruses were then injected into rat brain ventricles. From there, the viruses could infect cells in the ventricle walls, with the viral genes poised to replicate. Inside the brain cells, the adenoviruses began producing the two trophic factors using the cells? machinery.

Earlier research had shown that the protein BDNF [brain-derived neurotrophic factor] is needed to promote the emergence and survival of new neurons. Other studies had shown that the protein noggin inhibits the development of glial cells. The idea of Goldman?s team was to increase these two trophic factors (normally present in the brain at lower levels), to discourage the development of glial cells through the presence of noggin, and to encourage the development of neurons through the presence of BDNF at the same time.

The exciting finding of this research was that, not only did many new neurons develop, they integrated with the nearby brain area, the striatum, and they developed specifically into medium spiny neurons in the striatum. These are the neurons and the brain region most affected in Huntington?s disease. Moreover, the newly developed neurons established exactly the types of connections that medium spiny neurons normally form in the human brain, and they began functioning in ways like normal medium spiny neurons, including in the neurotransmitter they use (the neurotransmitter GABA).

These findings may provide great benefits for people with Huntington?s down the pike. However, to realize their promise will require additional research steps and clinical trials. Dr. Goldman?s lab at the University of Rochester is now testing the experimental protocol described above specifically in R6/2 model Huntington?s mice. Beyond these fascinating horizons, gene therapy covers still more ground than Huntington?s alone, and developments elsewhere in this field may also help accelerate HD therapies.

In the meantime, the present research results may provide further support for BDNF?s value in slowing and mitigating HD. A number of actions that people can take right now are known to raise BDNF levels (see relevant links to the Lighthouse webpages below).

The abstract of the research paper by Goldman and colleagues follows. The full article can be found at http://www.jneurosci.org/cgi/content/full/24/9/2133 .

(For more on gene therapy, see http://en.wikipedia.org/wiki/Gene_therapy. For more on BDNF?s supporting the growth of new neurons and on the roles of BDNF in Huntington?s disease, see .../research/brain/updates/1202bdnf.php and .../research/drugs-supps/updates/1206neurotrophins.php. To increase BDNF levels using safe, available measures, see .../see/drugs/bdnfdrugs.htm, .../treatment-care/care/hdltriad/exercise/updates/1243bdnf.php, and .../TreatmentNow/updates/0085-SSRItreatment.php.)

Ann Covalt, M.A.
Adenovirally Expressed Noggin and Brain-Derived Neurotrophic Factor Cooperate to Induce New Medium Spiny Neurons from Resident Progenitor Cells in the Adult Striatal Ventricular Zone
E. Chmielnicki, A. Benraiss, A. N. Economides, and S. A. Goldman
Neurogenesis from endogenous progenitor cells in the adult forebrain ventricular wall may be induced by the local viral overexpression of cognate neuronal differentiation agents, in particular BDNF. Here, we show that the overexpression of noggin, by acting to inhibit glial differentiation by subependymal progenitor cells, can potentiate adenoviral BDNF-mediated recruitment of new neurons to the adult rat neostriatum. The new neurons survive at least 2 months after their genesis in the subependymal zone and are recruited primarily as GABAergic DARPP-32+ medium spiny neurons in the caudate-putamen. The new medium spiny neurons successfully project to the globus pallidus, their usual developmental target, extending processes over several millimeters of the normal adult striatum. Thus, concurrent suppression of subependymal glial differentiation and promotion of neuronal differentiation can mobilize endogenous subependymal progenitor cells to achieve substantial neuronal addition to otherwise non-neurogenic regions of the adult brain.
The Journal of Neuroscience, March 3, 2004, 24(9):2133-2142