From The Quarterly, Summer 2011

The adult mammalian brain can generate new cells, an ability crucial to healthy brain functioning but one that can be compromised by aging or illness. In the June 24 issue of the journal Cell, Brain & Behavior Research Foundation Independent Investigator Hongjun Song, Ph.D., and colleagues report discoveries that are helping to explain how the brain renews itself.

Neurons are the all-important cells of brain communication. They are surrounded by glia, cells that provide support and protection. Adult neurogenesis and gliogenesis─the birth processes of neurons and of glial cells─occur in different brain regions. Stem cells are precursor cells that have the capacity to replicate themselves and also to mature into different specialized cell types. But whether neurons and glial cells arise from different types of progenitor cells or from a single type has been unclear until the current study.



Dr. Song is Professor of Neurology and Director of the Stem Cell Biology Program at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. Using mice as their model system, Song and his team developed a genetic strategy for tracing the life cycle of precursor cells in the brain. What they found was that any single stem cell is capable of both replacing itself and of giving rise to both neurons and glia. They also discovered that a lone stem cell can generate two new stem cells; that is, stem cells don’t just maintain the numerical status quo, or deplete in number, they can amplify their number.



In discussing this last, unexpected finding, Dr. Song observed: “If we can somehow cash in on this newly discovered property of stem cells in the brain, and find ways to intervene so they divide more, then we might actually increase their numbers instead of losing them over time, which is what normally happens, perhaps due to aging or diseases.”



In a needle-in-the-haystack approach, the researchers circumvented the problem of the enormous haystack represented by the many cell types in the mouse brain by using as their “needle” just one type of cell, called a radial glia-like precursor, or RGL. They chose to follow the fate of this particular cell based on earlier research showing that RGLs act in stem-cell fashion and give rise to neurons. Through genetic manipulation it was possible to color-code the cells, and track all the new cells generated by each original RGL. The labeled cells were followed for periods ranging up to a year during which they continued to produce progeny.   



To explore how RGLs were activated, the scientists focused on the role of a regulatory gene called PTEN (interestingly, an autism-associated gene.)  Previously, it had been thought that deleting PTEN increased stem-cell activation, but the Song team showed that the increase is transient and the ultimate effect of PTEN deletion is stem-cell depletion.



Dr. Song received a NARSAD Independent Investigator Grant in 2008.