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Open Access Publications from the University of California

When the Microenvironment Talks, Do Neural Stem Cells Listen? Novel Roles for Complement and Immune Interactions in Autocrine Regulation and Paracrine Modulation of Neural Stem Cells

  • Author(s): Benavente Perez, Francisca
  • Advisor(s): Anderson, Aileen J
  • et al.

Neural stem cell (NSC) therapies offer promising potential for promoting neurorepair following a variety of neurodegenerative disorders and central nervous system (CNS) injuries. As the use of NSC in clinical trials increases, it is critical to understand the basic biology underlying the neural stem cell capacity for self-renewal, migration, differentiation and final integration in the neural circuitry. Even though there is a great understanding of the molecules and factors involved in neurogenesis in the developmental neurogenic niche, little is known about how the changes in the neurogenic niche in response to disease, injury or aging, may modulate endogenous as well as transplanted NSC and their final capacity for neurorepair. Historically the CNS has been seen as an immuno-privileged organ, with limited interaction with immune components from the rest of the organism. However, it is clear that this view is incomplete and fails to encompass the dynamic and persistent immune response observed in the pathogenesis associated with many types of CNS diseases (e.g., Alzheimer’s disease, traumatic CNS injury, stroke, aging, etc.). We have shown that the inflammatory microenvironment affects NSC fate and migration, influencing their final capacity for neurorepair. We have previously identified a direct and interactive effect of complement components C1q and C3a on NSC mediating proliferation, migration and fate potential in vitro as well as in vivo with function blocking antibodies.

In this dissertation I investigate the molecular mechanisms associated with the effects of C1q and C3a on NSC, focusing on the ligand-receptor interactions responsible for this novel effect between the immune system and NSC populations. This dissertation is composed of an Introduction (Chapter 1), and three data chapters (Chapters 2-4) investigating a novel proposed cellular mechanism in which complement molecules modulate NSC migration, proliferation, fate, and final functional integration through direct interaction with cell surface receptors.

Elucidating NSC inflammatory microenvironment interactions (i.e, signaling molecules, receptors, intracellular pathways) will provide a better understanding of the impact of the inflammatory microenvironment on NSC populations. Understanding these mechanisms may be a key approach to enabling effective NSC therapies in CNS trauma, disease and aging.

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