Cerebrospinal fluid directs neural stem cell development

The clear, watery substance that bathes the brain and spinal cord is called cerebrospinal fluid.  This fluid is crucial for transporting gases and nutrients to the central nervous system, but it also turns out to affect neural stem cells.

Howard Hughes Medical Institute (HHMI) investigator Christopher Walsh, and his postdoctoral fellow Maria Lehtinen, former student Mauro Zappaterra, and colleagues have discovered that cerebrospinal fluid or CSF contains a complex mix of proteins that changes dramatically with age. In the lab, CSF by itself is enough to support the growth of neural stem cells, and this effect is particularly robust in young brains.

Additionally, these experiments discovered that the protein make-up of CSF in people with malignant brain cancer is different from that of healthy people.  “This suggests that the CSF can make a more supportive or less supportive environment for tumor growth,” notes Walsh, Chief of Genetics at Children’s Hospital Boston. The work is published in the March 10, 2011, issue of the journal Neuron.

Today, most researchers think of it as a relatively simple salt solution that gives the brain buoyancy and helps protect it from knocking against the skull.  However, several years ago, research on brain development conducted by Walsh’s group showed that there is much more to CSF.  Walsh and his colleagues noticed that neural stem cells tend to line up around the brain’s inner chambers, where CSF is stored, and stick cellular fingers, called cilia, into the pool of CSF. “That made us think, there’s got to be something in CSF that’s binding to cilia and controlling how the cell divides,” Walsh says.

In 2007, Zappaterra and Walsh performed the first comprehensive analysis of embryonic human CSF. Embryonic human CSF contains hundreds of different proteins, including proteins that influence cell growth, transport, support, and signaling. Walsh said, “We were amazed at the diversity of substances that we identified in there, many of which people had no clue would be there.”

In this new study, Walsh and his colleagues isolated small sections of embryonic rat brain tissue and cultured them with CSF from rats of different ages. When brain stem cells were bathed in CSF from young rats, they furiously divided, but when grown on CSF from older rats, there is less cell division.  Nevertheless, CSF from all ages contained all that is needed to maintain brain stem cells in a dish. Subsequent analysis of the fluid showed that the amount of a protein called Insulin-like growth factor 2 (Igf2) strongly correlates with the level of cell division, suggesting that this protein can be used to stimulate the division of neural stem cells in older patients.

The researchers then teamed up with Eric Wong’s groupfrom Beth Israel Deaconess Medical Center that has a bank of CSF samples isolated from people with various stages of glioblastoma, a type of brain cancer in which tumors infiltrate the whole brain. Wong’s group found that people with more advanced cancer have higher levels of Igf2 in CSF than do those with less severe forms of the disease.

It is presently still unknown if the increase in Igf2 levels is partly causing the cancer, or is instead a consequence of living with the disease. “We certainly don’t think Igf2 is the only contributor to the pathology, because glioblastomas are very complex. But it may be an interesting biomarker to consider,” says Maria Lehtinen, who is a joint first author of the study, along with Zappaterra.

Taking a closer look at CSF could be helpful in other brain diseases as well. Some researchers are investigating whether the levels of certain proteins, like Tau and Beta amyloid, might be used as predictors of Alzheimer’s disease, for example.

Because CSF is made by a tiny knob in the brain’s chambers called the choroid plexus,which constitutes the interface between the bloodstream and the brain—it could explain part of the mystery of how changes in the body link up to the brain. For example, if you exercise a lot, you form more brain cells, but no one knows exactly how this works.