Neural stem cells (NSCs) exist naturally in the adult human brain and have the potential to become multiple different types of brain cells, including neurons, astrocytes, and oligodendrocytes. The process of a NSC becoming a neuron in a mature brain is known as adult neurogenesis. Even before they have started to differentiate into their terminal cell type, NSCs have the ability to clear away cells that are dying from their surroundings by engulfment. Using cell culture and biomolecular methods this study seeks to understand whether NSC engulfment of dead cells affects their own differentiation. It is hypothesized here that the engulfment of the dead or dying cell will dictate the fate assumed by NSC when it differentiates into an adult cell. It is also important to know what part of the dying cell the engulfing cell is sampling in order to understand the identity of and effect of factors that are influencing its differentiation potential. This will be investigated by feeding different parts of dead cells to NSCs and then examining the differentiation outcomes. Understanding how a cell adopts its mature form is fundamental to our understanding of how all multicellular organisms develop from a single initial pluripotential stem cell that has the ability to develop into multiple different cell types. The novel ideas proposed in this study have the potential to shed new light on our understanding of neurogenesis in a regenerating system. Findings uncovered here could have wider application to differentiating progenitor cells in other regenerating or developing organ systems. Thus, this study will further the understanding of how all stem cells turn into their ultimate cell types. This project will provide training opportunities for post-graduate, graduate, and undergraduate students in a field that uses cutting-edge scientific tools and intense scientific interactions. It will also offer mentoring opportunities for high school students who participate in summer programs that seek to encourage women to pursue careers in basic science, including physics, and engineering.
Adult neurogenesis occurs primarily in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the hippocampal dentate gyrus. In these areas of the brain, neural progenitor cells are multi-potent, with the potential to become astrocytes, oligodendrocytes, or neurons. The biology of neural progenitors is fascinating and under constant investigation. Every new piece of information reveals more questions than answers, and we are constantly facing breakthroughs in this field. The process of neurogenesis is on its own one of the major puzzles of the modern science. How the process is maintained and what ensures proliferation and differentiation of neural progenitor cells is largely unknown. Our proposed hypothesis was to test the role of phagocytosis, recently discovered by our lab to maintain adult neurogenesis, in fate-commitment of the progenitor cells. Recently, we have shown that neuronal progenitor cells actively phagocytose the apoptotic bodies of neighboring cells. Pharmacological and genetic blocking of this phagocytic activity results in impairments in adult neurogenesis. During the life of this grant we showed that phagocytic activity of neural progenitors alters their survival and differentiation and is mediated a leak of genetic information from the eaten cell into the phagocyte. This project provided a unique training opportunity not only for the post-doctoral fellow and a graduate student, who were directly involved in this project, but also for undergraduate students, involved in this project. The students and fellow were exposed to cutting-edge scientific tools and intense scientific interactions. Such an extensive experience with scientific techniques along with deciphering an exciting, conceptually novel idea has undoubtedly provided an enriched scientific environment for those who were involved in the project.
