Researchers have figured out how to wake up dormant stem cells that have the ability to develop into new cells in the brain, opening the door to developing new therapies for neurodevelopmental disorders such as autism, learning disabilities and cerebral palsy.
Stem cells in the brain are called neural stem cells (NSCs) and have the ability to proliferate, differentiate, and undergo cell death. Most of the NSCs in our brain lie dormant, waiting for a signal that will reactivate them to undertake neurogenesis, or the formation of new nerve cells.
Evidence suggests that defective NSC reactivation may be associated with age-related cognitive decline and neurodevelopmental disorders, and therefore it is important to determine the mechanisms underlying the process. Now, researchers from the Duke-NUS Medical School and the Institute of Mechanobiology at the National University of Singapore (NUS) have gone even further and discovered a method to activate dormant NSCs.
“Our findings add new insights to the limited body of research on the mechanisms governing the reactivation of dormant neural stem cells,” said Professor Wang Hongyan, acting program director of the Duke-NUS Neuroscience and Behavioral Disorders Research Program and corresponding author of the study.
For the current study, the researchers conducted experiments on fruit flies (Fruit fly). Inside Fruit flyThe presence of dietary amino acids is sensed by the fat body, a functional equivalent of the human liver and adipose tissue, which triggers the production of insulin-like peptides by cells at the blood-brain barrier. These peptides, in turn, activate the insulin-like growth factor 1 (IGF-1) signaling pathway in NSCs and trigger their reactivation. Human NSCs are also activated by IGF-1 signaling.
Dormant NSCs Fruit fly has a protrusion extending from the cell body; researchers have recently shown that the protrusion is enriched with actin microfilaments. Actin is a protein that provides mechanical support and determines cell shape, among other functions. The organization of actin within cells is regulated by another type of protein called formin, which promotes the formation of a specific actin, filamentous actin (f-actin).
“We decided to focus on this pathway because variants in formin levels have been associated with neurodevelopmental disorders such as microcephaly in humans,” said Dr. Lin Kun-Yang, a research associate at Duke-NUS at the time of the study and lead author. Microcephaly is a condition in which a baby's head is significantly smaller than expected, usually due to abnormal brain development. “Understanding this pathway could provide new insights into developing solutions to treat neurodevelopmental disorders.”
Using super-high-resolution microscopy, the researchers examined cellular protrusions measuring about 1.5 µm in diameter, 20 times smaller than the diameter of a human hair. They found that astrocytes, a type of glial cell that holds neurons in place and helps them develop and function properly, produce a type of signaling protein called Folded gastrulation (Fog), which activates the formin pathway, triggering a chain reaction that controls the assembly of actin filaments and wakes NSCs from dormancy.
Receptors called G protein-coupled receptors, or GPCRs, on NSCs responded to Fog produced by astrocytes, activating a signaling pathway that regulates the formation of actin filaments in the stem cells.
“This not only advances our fundamental understanding of how astrocytes influence brain cell development, but also opens new avenues for advancing therapies for neurological disorders, brain ageing and injuries,” said Professor Patrick Tan, Senior Associate Dean for Research at Duke-NUS. Tan was not involved in the study.
GPCRs play a role in vision, taste, smell, behavior, mood, and immune system regulation. While the signaling molecules, types of GPCRs, and mechanisms of action differ for each of these roles, they all involve G proteins, which act as molecular switches and transmit signals from the outside to the inside of the cell. For this reason, GPCRs have become important drug targets to treat a variety of human diseases.
The researchers are currently investigating whether astrocytes produce other signals that influence the activity of NSCs, and they also plan to investigate whether similar mechanisms are involved in human brain development.
The study was published in the journal Science Advances.
Source: Duke-NUS Medical School