The discovery that new functional neurons arise daily in adult brains (see related ARF story) has raised hopes that endogenous stem cells may be coaxed to replace neurons lost or damaged by diseases such as Alzheimer's or Parkinson's. Unfortunately these hopes haven't lasted too long, given that adult neurogenesis takes place in just two distinct regions of the brain, the subgranular zone of the hippocampus and the subventricular zone, both of which are far from the sites of disease-related neurodegeneration. But what if, one day, we could induce neurogenesis in all regions of the central nervous system? Such a discovery would have immense consequences both for slow degenerative diseases and, for example, for the blunt trauma injuries that result in severed spinal cords. As is turns out, researchers at Fred Gage's lab at the Salk Institute in La Jolla, California, may have found a key to inducing CNS-wide neurogenesis-the astrocyte.

Gage and colleagues report in the May 2 Nature that astrocytes, long thought to play second fiddle to the neurons, are actually more like the conductors of the orchestra, deciding where and when stem cells should blossom into full-fledged neurons. It is known that adult neural stem cells can differentiate into one of three major cell lineages, neurons, oligodendrocytes, or astrocytes. The authors found that more stem cells turn into neurons when grown on layers of neonatal astrocytes than when grown on more traditional substrates, such as laminin or polylysine. In fact, Song et al. showed that neurons appeared eight times faster under the influence of the astrocytes, which was in part due to a greater proliferation of progenitors.

The authors also found that not all astrocytes have such a strong influence in deciding the fate of stem cells. Astrocytes from adult hippocampus were only about half as efficient as their neonatal counterparts, while those from adult spinal cord did not support neurogenesis at all. Why this may be is uncertain, but as Clive Svendsen from the University of Wisconsin in Madison points out in an accompanying News and Views, it could be related to the age of the astrocytes-in the spinal cord they are much older than in the hippocampus where they are constantly being made afresh. Ironically then, it may be the astrocytes that restrict adult neurogenesis to such localized regions.—Tom Fagan

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  1. I was not surprised by this paper. Though the abstract says, "This role in fate specification was unexpected," we have already indicated (Brannen & Sugaya, 2000) that astrocytes may contribute to cell fate regulation in human neural stem cells in vitro. We have reported a large population of GFAP-positive cells in earlier stages of differentiation under serum-free conditions and gradual increase in betaIII-tubulin-positive cells in later stages. This indicates that astrocytes may produce some factor(s) to induce neuronal differentiation in human neural stem cells in vitro. We also found that dying neurons produce AβPP fragments, which induced glial differentiation in the neural stem cells in the early stage of serum-free differentiation. We are hypothesizing that AβPP fragments produced by neuronal damage induce astrocyte differentiation or activation, and the activated astrocytes (some type of radial glia?) may recruit and differentiate the neural stem cell to replace the damaged neurons. This mechanism could be very important in adult neurogenesis, and the Song et al. paper proves a part of it in an elegant way.

    We have to understand not only the bad side of glial activation (inflammation of the brain), but also the beneficial side of glial activity (including regulation of stem cell biology) in relation to AD pathology. In another words, excess suppression of glial activity or AβPP processing may not be a cure for AD.

    References:

    . In vitro differentiation of multipotent human neural progenitors in serum-free medium. Neuroreport. 2000 Apr 7;11(5):1123-8. PubMed.

References

News Citations

  1. New Neurons in Old Brains Make New Contacts

Further Reading

Primary Papers

  1. . Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002 May 2;417(6884):39-44. PubMed.
  2. . The amazing astrocyte. Nature. 2002 May 2;417(6884):29-32. PubMed.