Researchers at Columbia University Medical Center (CUMC) have identified a molecular pathway that controls the retention and release of the brain's stem cells. The discovery offers new insights into normal and abnormal neurologic development and could eventually lead to regenerative therapies for neurologic disease and injury. The findings, from a collaborative effort of the laboratories of Drs Anna Lasorella and Antonio Iavarone, were published today in the online edition of Nature Cell Biology.
The research builds on recent studies, which showed that stem cells reside in specialised niches, or microenvironments, that support and maintain them.
''From this research, we knew that when stem cells detach from their niche, they lose their identity as stem cells and begin to differentiate into specific cell types,'' said co-senior author Antonio Iavarone, MD, professor of Pathology and Neurology at CUMC.
''However, the pathways that regulate the interaction of stem cells with their niche were obscure,'' said co-senior author Anna Lasorella, MD, associate professor of Pathology and Pediatrics at CUMC and a member of the Columbia Stem Cell Initiative.
In the brain, the stem cell niche is located in an area adjacent to the ventricles, the fluid-filled spaces within the brain. Neural stem cells (NSCs) within the niche are carefully regulated, so that enough cells are released to populate specific brain areas, while a sufficient supply is kept in reserve.
In previous studies, Drs Iavarone and Lasorella focused on molecules called Id (inhibitor of differentiation) proteins, which regulate various stem cell properties. They undertook the present study to determine how Id proteins maintain stem cell identity.
The team developed a genetically altered strain of mice in which Id proteins were silenced, or knocked down, in NSCs. In the absence of Id proteins, mice died within 24 hours of birth. Their brains showed markedly lowered NSC proliferative capacity, and their stem cell populations were reduced.
Studies of NSCs from this strain of mice revealed that Id proteins directly regulate the production of a protein called Rap1GAP, which in turn controls Rap1, one of the master regulators of cell adhesion. The researchers found that the Id-Rap1GAP-Rap1 pathway is critical for the adhesion of NSCs to their niche and for NSC maintenance. ''There may be other pathways involved, but we believe this is the key pathway,'' said Dr Iavarone. ''There is good reason to believe that it operates in other kinds of stem cells, and our labs are investigating this question now.''