Neuron-producing stem cells in the brain are controlled by a host of mechanisms, and two of these have been more precisely enumerated thanks to work by Steven Levison and Teresa Wood at the University of Medicine and Dentistry of New Jersey and Anna Lasorella at Columbia University Medical Center.
The first study by Levison and Wood examined proteins that are soluble in the cerebrospinal fluid. Neural stem cells are in constant contact with the cerebrospinal fluid, and therefore, any signaling molecules that are secreted into the cerebrospinal fluid (CSF), can potentially influence the activity of neural stem cells.
Insulin-like growth factors are typically made in response to growth hormone. Because these insulin-like growth factors mediate the response of growth hormone, they are called somatomedins. Insulin-like growth factors (IGFs) also play roles in the development of the brain. There are two main IGFs, IGF-1 and IGF-2. IGF-I and its receptor (IGF-IR) are widely expressed in the central nervous system, and IGF-2 is expressed in a more restricted pattern. IGF-binding proteins are similarly expressed during varying phases of brain development. IGF-I regulates both neuronal and glial cell proliferation and differentiation, apparently by an initial increase in neural progenitor proliferation. Loss of function mutations in the genes that encode either IGF-I or IGF-IR result in brain retardation, and overexpression leads to brain overgrowth. A few cases of IGF-I or IGF-IR mutations have been described in humans, and both of them result in some form of mental retardation and even microcephaly (small head). Later in development, circulating IGF-I levels are elevated and brain levels-specific are reduced, but circulating IGF-I can cross the blood-brain barrier and influence brain biology. It seems to prevent programmed cell death of neurons (see D’Ercole AJ, Ye P 2008 Minireview: expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149:5958–5962).
This study by Levison and Wood established that IGF-1 & 2 are essential for neural stem cell renewal and cell proliferation. IGF-1 maintains neural stem cell numbers by promoting cell division. However, IGF-2 drives the expression of those proteins necessary to main the undifferentiated state of the neural stem cells.
Since the concentration of both these proteins declines with age, it might explain the cognitive decline associated with aging.
The second study identified a molecular pathway that controls the retention and release of the brain-specific stem cells. Antonio Iavarone and Anna Lasorella at Columbia University Medical Center were able to establish that neural stem cells reside in small areas called “niches.” This molecular pathway also works to maintain the neural stem cell population.
According to Iavarone, “From this research, we knew that when stem cells detach from their niche, they lose their identity as stem cells and begin to differentiate into specific cell types.”
Stem cell niches in the brain are located right next to the “ventricles.” Ventricles are fluid-filled spaces within the central nervous system. These fluid-filled spaces are loaded with cerebrospinal fluid. the number of neural stem cells within these neural stem cell niches is carefully regulated so that enough cells are present for cell division, but enough are released into the brain to replenish dead or heavily-needed neurons. However, as explained by Anna Lasorella, associate professor of pathology and pediatrics, “the pathways that regulate the interaction of stem cells with their niche were obscured.”
In previous work, Iavarone and Lasorella showed that molecules called ID or inhibitor of differentiation proteins, regulate stem cell properties (Iavarone A, Lasorella A. Trends Mol Med. 2006 Dec;12(12):588-94). This present study determined how Id proteins regulate stem cell identity.
In this study, mice with loss-of-function mutations in the gene that encodes the Id protein. They also made strains in which the amount of the Id protein was not eliminated, but decreased. In the mice with no ID protein, the mice died within 24 hours of birth. The brains of these mice showed very low levels of neural stem cell proliferation and the entire neural stem cell population was greatly reduced.
When Iavarone and Lasorella and their co-workers examined what genes were reduced in the absence of Id proteins, they discovered some of these genes encoded proteins involved in cell adhesion. Therefore the Id proteins brings on-line a whole host of proteins that cause the neural stem cells to stick to their stem cell niche., This adhesion allows the neural stem cells to divide and increase in numbers. However, the Id protein is not completely segregated to the sister cell and this cell does not express the cell adhesion genes and detaches from the stem cell niche. The detachment from the stem cell niche induces differentiation in the neural stem cell, and the specific cell type it forms depends upon microenvironmental cues.
Therapeutic application of these finds will require a good deal more research. Dr. Iavarone said. “Multiple studies show that NSCs respond to insults such as ischemic stroke or neurodegenerative diseases. If we can understand how to manipulate the pathways that determine stem cell fate, in the future we may be able to control NSC properties for therapeutic purposes.”
“Another aspect,” added Dr. Lasorella, “is to determine whether Id proteins also maintain stem cell properties in cancer stem cells in the brain. In fact, normal stem cells and cancer stem cells share properties and functions. Since cancer stem cells are difficult to treat, identifying these pathways may lead to more effective therapies for malignant brain tumors.”
Stephen G. Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital & Columbia University Medical Center, added that, “Understanding the pathway that allows stem cells to develop into mature cells could eventually lead to more effective, less toxic cancer treatments. This beautiful study opens up a wholly unanticipated way to think about treating brain tumors.”