Understanding mechanisms of microglia regulation : neural progenitor cells and molecular changes in the aging systemic environment regulate microglial activity - Mosher, Kira Lin Irvin; Wyss-Coray, Anton; Andreasson, Katrin; Palmer, Theo; Steinman, Lawrence; Stanford University, Neurosciences Program (2014)
Microglia are the resident immune cells of the central nervous system. This unique population of cells has been implicated in some way in every neurodegenerative disorder, but they are also essential for proper neural development and for maintaining homeostasis in the healthy adult brain. To assume such distinct roles, the range of microglial effector functions is impressively diverse, and includes the capacity for proliferation, motility, the secretion of both pro- and anti-inflammatory factors, and phagocytosis. The execution of these functions is based upon the detection of signals from their microenvironments, which microglia are particularly well equipped to recognize. Thus microglia are remarkably versatile in terms of both their sensory abilities for external cues and their functions in response to these signals. Understanding the mechanisms by which these cells are controlled is therefore a primary goal in the field of microglial biology and will also be essential for harnessing microglial functions in disease states. The studies presented in this dissertation aim to elucidate the regulation of microglial behavior through extrinsic signaling mechanisms at multiple levels: the first at the level of a defined molecular niche within the brain, and the second within the context of the systemic signaling environment of the organism as a whole. In the first study, we demonstrate the integral relationship between microglia and neural progenitor cells (NPCs). Microglia are known to influence some functions of NPCs, which in the adult mammalian brain reside within specific neurogenic niches. We found that NPCs themselves are in fact capable of secreting a distinct profile of immunomodulatory proteins and are powerful modulators of microglial activity and functions. In the second study, we investigate mechanisms of microglial regulation in the aging organism. We found that aging is accompanied by a general increase in neuroinflammation and microglial dysfunction. Some of these microglial alterations may be mediated, in part, by age-related changes in the levels of bloodborne proteins of the systemic environment. Furthermore, we show that manipulation of the molecular composition of the systemic environment through heterochronic parabiosis can accelerate in young animals, or reverse in old animals, microglial aging phenotypes. Collectively, this work highlights the regulation of microglial phenotypes and functions through signaling mechanisms occurring at both the cell-to-cell and system-wide level. These findings will not only expand our general understanding of microglial biology but could also have implications for the development of therapeutic interventions to control microglia in disease states.
Submitted to the Neurosciences Program.
Thesis (Ph.D.)--Stanford University, 2014.
Rights: (c) Copyright 2014 by Kira Lin Mosher
Rights: This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Keywords: theses