One of the fundamental challenges in developing stem cell-based medical treatments is controlling how stem cells divide and produce specialized cells. Now, neuroscientists at City of Hope have discovered a control mechanism in neural stem cells that is critical to this cell-fate decision.

The team’s findings were published online in the journal Nature Structural & Molecular Biology.

Yanhong Shi studies how the protein TLX controls the fate of neural stem cells. (Photo by Paula Myers)

“Our continuing studies revealed that TLX and a specific microRNA interact to control neural stem cell proliferation and differentiation,” said Shi, the paper’s senior author. “It may be possible to control neural stem cell fate through control of a microRNA.”

MircoRNAs are short strands of RNA that can regulate gene expression to affect normal development or diseases. “The role of microRNAs in neural development began being unfolded recently,” said Chunnian Zhao, Ph.D., a research fellow in neurosciences and the paper’s first author. “The interplay of TLX and miR-9, a microRNA specific to brain cells, provides novel insights into understanding the regulation of neural stem cells by microRNAs.”

Neural stem cells produce new cells in two ways. They can make new stem cells in a process known as proliferation, or they can make new neurons and glial cells through a process known as differentiation. The ability to control the production processes of neural stem cells could lead to improved stem cell-based therapies for neurodegenerative diseases and targeted brain tumor treatments.

Shi’s laboratory team found that TLX and miR-9 respond to each other, forming a feedback loop that controls neural stem cell proliferation and differentiation.

While TLX activity promotes proliferation, it also suppresses miR-9 expression. At the same time, expression of miR-9 suppresses TLX activity and promotes differentiation. This interaction between TLX and miR-9 keeps neural stem cell activity in balance and presents researchers with the method through which stem cell production can be controlled. This study is the first demonstration of a microRNA-transcription factor-based regulatory loop to determine the fate of neural stem cells.

Neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases affect millions of Americans. These diseases kill neurons in the brain and spinal cord, which can lead to loss of motor control, memory and ability to learn and carry out daily activity. The rate of cell loss eventually overcomes the natural pace of neural stem cell production, but being able to control the stem cell process may help in developing effective treatments against these conditions.

“In our continuing research of the feedback regulatory loop, we are investigating if the process is similar or different in normal neural stem cells and brain tumor stem cells at the source of brain tumor,” said Shi. “We want to eventually develop microRNA-based therapies that take advantage of this feedback loop to control or even shut down cancer stem cells.”

Understanding the TLX and miR-9 interaction in normal neural stem cells has potential to help develop therapies for brain tumors. The American Cancer Society estimated that more than 21,000 people were diagnosed with brain tumors in 2008, and more than 13,000 patients died from the disease. The current 5-year survival rate for brain tumor patients is 35 percent. Small RNA molecule drugs, such as microRNAs, may offer potential benefits in treating this disease.

“TLX and miR-9 are specific to the neurogenic regions of the brain, but the basic regulatory control model could be similar in other types of stem cells,” said Shi. “This study is important not only in the field of neural stem cells but also as a general concept with potential application in other areas of stem cell research.”

The study is available on www.nature.com/nsmb.