Stem cells have the remarkable ability to remain forever young until coaxed into adult roles as nerve, muscle or blood cells. Scientists call this seemingly magical flexibility “stemness.”
But while the concepts of “happiness” and “kindness” are best left unexplained, preserving the mystery around “stemness” hampers efforts to develop lifesaving therapies for conditions such as neurodegenerative disease. One City of Hope investigator is doing her best to dispel the mystery by identifying the factors behind neural stem cells’ eternal youth.
Yanhong Shi, Ph.D., assistant professor in the Division of Neuroscience, recently reported in Proceedings of the National Academy of Science how a protein called TLX maintains a critical component of “stemness,” namely, neural stem cells’ ability to divide over and over, or “self-renew.”
Until recently, scientists thought that once an adult lost nerve cells in the brain or spinal cord — whether through trauma, disease or aging — the cells were irreplaceable. That assumption has now been disproved.
“The first challenge came in 1965, but major cracks in the dogma came in the early 80s when it was found that some songbirds can make new neurons in the adult brain. Subsequently, neural stem cells were found in adult mammalian brains,” Shi said. “These cells have the ability to self-renew and differentiate into brain cells like neurons.”
As a postdoctoral fellow at the Salk Institute, Shi discovered that lab mice engineered to lack TLX have far fewer neural stem cells in the adult brain, implying that neural stem cells require the protein to renew themselves. Her new study reports that to keep neural stem cells youthful, TLX partners up with another protein called a histone deacetylase (HDAC).
Shi and City of Hope postdoctoral fellow Guoqiang Sun, Ph.D., the first author of the PNAS study, showed that TLX and HDAC act as a team to put the brakes on expression of two genes that encourage neural stem cells to mature into adult nerve cells.
Interestingly, one of those two genes — called pten — is also what is known as a tumor suppressor gene, a gene that protects cells against cancer.
This intriguing finding could mean that the duo of TLX and HDAC controls not only the renewal of healthy stem cells that regenerate tissues, but also the activity of a more sinister type of cell that gives rise to a tumor, known as a “cancer stem cell.”
“This is a very important finding about mechanisms of how neural stem cells maintain stemness,” said Sun. “It could lead to potential drug discoveries — in one direction, for tissuereplacement therapies for diseases like Alzheimer’s or Parkinson’s, or in another, to target cancer stem cells.”
Shi notes one big practical hurdle challenging scientists who want to use stem cells to grow replacement tissue is that it is difficult to acquire enough adult neural stem cells.
“Knowing how neural stem cell growth is regulated — how cells proliferate and self-renew — is critical,” she said. “This study provides targets that can be used to regulate how efficiently stem cells self-renew.”
Also contributing to the study were Ruth Yu, Ph.D., and Ronald Evans, Ph.D., of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies.
Sun is the recipient of the Herbert Horvitz Postdoctoral fellowship for neuroscience research. Additional funding for the study came from a grant to Shi from the National Institutes of Health National Institute of Neurological Disorders and Stroke.
