Researchers in City of Hope’s Department of Neurosciences took a significant step forward in understanding how brain stem cells remain in their primitive stages while still growing and multiplying. The work, reported Dec. 13, 2009, in the online edition of Nature Cell Biology, is an important advance in the quest for stem cell therapies.

Yanhong Shi studies how neural stem cells self-renew. (Photo by Paula Myers)

The research and medical communities have long touted the promise of stem cells for curing a multitude of diseases ranging from cancer and diabetes to spinal cord injury and neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Stem cells’ healing potential arises from their ability to develop, or differentiate, into many different cell types in the body, such as nerve, muscle and blood cells. This ability lets them repair and replenish injured tissues and organs.

For the body to repair and replenish itself under normal conditions, however, it must maintain a continuous supply of self-renewing stem cells; that is, stem cells that are fresh and ready to develop into other cell types, but only when needed. So, stem cells must face a choice as they grow: continue to renew themselves by multiplying as stem cells, or differentiate into other cell types.

Controlling this decision point is important for researchers; it will allow them to grow vast numbers of self-renewing, undifferentiated stem cells that are young and ripe for treating disease.

“One of the biggest challenges to stem cell therapies is simply having enough stem cells,” said Yanhong Shi, Ph.D., assistant professor of neurosciences and senior author on the study. “We need to know how to expand them in order to apply them to therapies.”

Until now, scientists were not sure what signaled neural stem cells — stem cells that eventually can become nerve and brain cells — to simply renew themselves and grow without differentiating. Shi and her team believe they have found the controlling signal.

The process begins with a protein called TLX, which controls key genes in neural stem cells. In previous work, Shi and her team found that TLX was essential to keeping neural stem cells growing in the self-renewal phase.

In the current study, the researchers discovered that TLX activates an important molecular pathway called Wnt/β-catenin.

“Wnt proteins have been shown to control the self-renewal of several types of stem cells, including blood-forming stem cells and skin stem cells,” said Shi. The current study is the first to connect TLX and Wnt proteins in self-renewing neural stem cells.

The discovery that the TLX-Wnt/β-catenin pathway stimulates neural stem cell growth and self-renewal suggests ways for researchers to manipulate neural stem cells to keep them growing and renewing themselves without differentiating.

According to Shi, knowing the signals and molecular pathways that keep stem cells self-renewing is crucial to developing a large enough supply of stem cells to treat patients, and the current work marks a major step toward that goal.

Collaborators include scientists from Howard Hughes Medical Institute and the Salk Institute. The Whitehall Foundation, the Margaret E. Early Medical Trust and the National Institute of Neurological Disorders and Stroke supported the work.