Doetsch Lab Illuminates Niche Where Neurons Are Made

NEW YORK (Sept. 11, 2008) - New work from the laboratory of Fiona Doetsch, Ph.D., assistant professor of pathology and cell biology in neurology and neuroscience at Columbia University Medical Center, uncovers novel and unexpected features of the neural stem cell niche in the largest neurogenic region of the adult brain, the subventricular zone (SVZ). The work, published in the Sept. 2008 edition of Cell Stem Cell, by Dr. Doetsch and her colleagues has potential clinical implications for understanding and treating multiple sclerosis, other neurodegenerative diseases and possibly cancer, as well as understanding the regulation of stem cells in the adult brain.

In this image of brain tissue, dividing stem cells and transit amplifying cells, seen here in green, are shown in direct contact with blood vessels. Credit: Doetsch Lab at CUMC Contrary to what was believed for many years, it turns out that adult mammals -- including humans -- generate new neurons throughout life, a process called neurogenesis. Neurogenesis only occurs in restricted brain areas in specialized microenvironments called niches. Stem cells residing in these niches are the source of adult-born neurons. Little is known about what makes these niche regions uniquely fertile for the formation of neurons. Uncovering the niche and regulation of adult neural stem cells is key to understanding their biology and will be essential to harness them for brain repair.

Neurons are the cells that are lacking or dysfunctioning in many neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Huntington's disease and Parkinson's disease.

In previous work, Dr. Doetsch has identified the stem cells and lineage for adult neurogenesis, as well as the migration pathways the new neurons take from their site of birth to remote areas where they integrate into the brain's circuitry. Dr. Doetsch and colleagues now have found that blood vessels are a key component of the SVZ stem cell niche and are different from blood vessels in other areas of the brain. Her lab has developed a method to reveal the three-dimensional architecture of this brain region, showing tight coupling with blood vessels in the stem cell niche. This led Dr. Doetsch and her colleagues to ask if anything is special about the blood vessels that are near where adult neurogenesis occurs.

Fiona Doetsch, Ph.D., in her lab at CUMC. Credit: Doetsch Lab at CUMC The brain is more isolated from circulation than the rest of the body due to the blood-brain barrier, which prevents most of what is circulating in the blood from exiting the vessels and entering the brain. They found that both under normal conditions and during regeneration, stem cells and transit amplifying cells directly contact blood vessels at sites that lack glial endfeet, a component of the BBB.

They hypothesized that a modified blood-brain barrier might be a key aspect of the niche that nurtures adult neurogenesis. Strikingly, they found that small molecules enter the SVZ stem cell niche directly from the circulation, which does not occur in other areas of the brain. Stem cells and their progeny in this niche therefore likely have privileged access to a variety of signals from blood vessels, which play a vital role in the creation of new neurons in the adult brain.

“This is an important step forward in understanding why certain regions of the brain are able to continuously generate new neurons” says Dr. Doetsch. “Our hope is that by understanding the in vivo biology of adult neural stem cells, we can learn how to steer new neurons to other brain areas, and to locally activate stem cells in brain areas that do not normally make neurons.”

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