Specific regions within the adult mammalian brain maintain the ability to generate neurons. The larger of these, the subventricular zone (SVZ), comprises the entire lateral walls of the lateral ventricles. Here a subset of astrocytes (B cells) gives rise to neurons and oligodendrocytes throughout life. These cells represent a pool of stem cells that could potentially be used to regenerate lost neural tissue following neurodegenerative disease, stroke, or trauma. Stem cells and their progeny have also been proposed to underlie the formation of high- grade brain tumors, such as glioblastomas. In order to understand the therapeutic potential of this niche it is essential to understand the biology of the quiescent neurl stem cells (qNSCs) and how they become activated. Unfortunately, studying these cells has been hindered by the lack of specific markers to identify them. Here we propose that platelet-derived growth factor receptor beta (PDGFR?) is one such marker. Based on the analysis of putative qNSC populations and experiments using a blocking antibody against the receptor, we hypothesize that PDGFR? is a marker of qNSCs and that it regulates their quiescent state. We will first determine whether PDGFR?-positive B cells are quiescent cells within the SVZ through analyses of their cell cycle state. We will then lineage trace adult SVZ PDGFR?-positive B cells to determine what cell types (i.e. neurons, astrocytes, and/or oligodendrocytes) they give rise to during homeostasis and regeneration. Lastly, we will determine what the function of PDGFR? is in the adult SVZ by genetically altering PDGFR? levels specifically in B cells. Together these studies will provide information on the identity and regulation of these quiescent neural stem cells.
Endogenous adult neural stem cells offer therapeutic potential in the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, as well as in stroke and traumatic brain injuries. These cells have also been suggested to underlie glioblastomas and other brain tumors that possess high mortality rates. Understanding their regulation and function could help provide therapies for brain repair and insight into the treatment of the above pathological processes.
|Silva-Vargas, Violeta; Maldonado-Soto, Angel R; Mizrak, Dogukan et al. (2016) Age-Dependent Niche Signals from the Choroid Plexus Regulate Adult Neural Stem Cells. Cell Stem Cell 19:643-652|
|Maldonado-Soto, Angel R; Oakley, Derek H; Wichterle, Hynek et al. (2014) Stem cells in the nervous system. Am J Phys Med Rehabil 93:S132-44|
|Codega, Paolo; Silva-Vargas, Violeta; Paul, Alex et al. (2014) Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron 82:545-59|