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 specialized 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."
"This is a new idea," added Dr. Lasorella. "Before this study, the prevailing wisdom was that NSCs are regulated by the niche components, conceivably through the release of chemical attractants such as cytokines. However, our findings suggest that stem cell identity relies on this mechanism."
More research needs to be done before the findings can be applied therapeutically, Dr. Iavarone said. "Multiple studies show that NSCs respond to insults such as ischemic stroke or neurodegenerative diseases. If we can understand how to manipulate the pathways that determine stem cell fate, in the future we may be able to control NSC properties for therapeutic purposes."
"Another aspect," added Dr. Lasorella, "is to determine whether Id proteins also maintain stem cell properties in cancer stem cells in the brain. In fact, normal stem cells and cancer stem cells share properties and functions. Since cancer stem cells are difficult to treat, identifying these pathways may lead to more effective therapies for malignant brain tumors."
Stephen G. Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, added that, "Understanding the pathway that allows stem cells to develop into mature cells could eventually lead to more effective, less toxic cancer treatments. This beautiful study opens up a wholly unanticipated way to think about treating brain tumors."
The paper is titled "Id proteins synchronize stemness and anchorage to the niche of neural stem cells." Other contributors are Francesco Niola (CUMC), Xudong Zhao (CUMC), Devendra Singh (CUMC), Angelica Castano (CUMC), Ryan Sullivan (CUMC), Mario Lauria (Telethon Institute of Genetics and Medicine, Naples, Italy), Hyung-song Nam (Memorial Sloan-Kettering Cancer Center, New York),, Yuan Zhuang (Duke University Medical Center, Durham, North Carolina), Robert Benezra (Memorial Sloan-Kettering), and Diego Di Bernardo (Telethon Institute of Genetics and Medicine).
This research was supported by National Cancer Institute grants R01CA101644, R01CA131126, R01CA085628, and R01CA127643, and National Institute of Neurological Disorders and Stroke grant R01NS061776.
The authors declare no financial or other conflicts of interest.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States.
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