DUARTE, Calif., March 29, 2009 — One of the fundamental challenges in developing all stem cell-based medical treatments is controlling the process by which they copy themselves and produce specialized cells. Neuroscientists at City of Hope have discovered the control mechanism in neural stem cells that enable them to either make new neurons or more copies of themselves. The ability to control the production process of neural stem cells could lead to improved stem cell-based therapies for neurodegenerative diseases and targeted brain tumor treatments. The study appears online in the journal Nature Structural & Molecular Biology (www.nature.com/nsmb) in advance of its publication in the print edition.
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. When neural stem cells produce new cells they can either make new stem cells, in a process known as proliferation, or they can make new neurons and glial cells that support and protect neurons, in a process known as differentiation.
“We found in previous studies that a transcription factor called TLX is an essential regulator of neural stem cell self-renewal. Our continuing studies revealed TLX and a specific microRNA interact to control neural stem cell proliferation and differentiation,” said Yanhong Shi, Ph.D., assistant professor, Department of Neurosciences, City of Hope, and senior author of the study. “It may be possible to control neural stem cell fate through control of 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 to be unfolded recently. The interplay of TLX and miR-9, a microRNA specific to brain cells, provides insights into understanding the regulation of neural stem cells by microRNAs.” said Chunnian Zhao, Ph.D., a research fellow in neurosciences and first author of the study. 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.
“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 the tumor,” said Shi. “We want to eventually develop microRNA-based therapies that take advantage of this feedback loop to control or even shut down the cancer stem cells.”
Developing therapies that control the TLX and miR-9 interaction in normal healthy neural stem cells has potential to help with brain tumors as well. 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. The blood-brain barrier prevents large molecules from entering the brain, which keeps out many toxic compounds that can cause harm. The barrier also blocks most chemotherapy compounds from entering the brain to kill off tumor cells. Small 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.
