Bioengineering an improved niche for neural stem cells

Aging is one of the key drivers of cognitive decline and slowing neurogenesis. It is a major risk factor for neurodegenerative diseases. In the process of aging, neural stem cells stop proliferating at a high level, and the niche surrounding them begins to undergo extensive change. This large shift consists of vascular changes, lower growth factor signaling, higher stiffness and tension, and reduced cell-to-cell interactions. In research to date, in vitro models have not recreated a full neural stem cell niche while taking into account all of the previously listed factors. In this proposal, a bioengineered, 3D niche specifically designed to recreate the environment of a young neurogenic niche is constructed. The niche will have the stiffness of its hydrogel extracellular matrix tuned, growth factors added and co-culturing of glial cells with neural stem cells. The neural stem cells, from aged mice and from young mice, will be sowed into the target niche and two controls, which will be developed into organoid systems. Measurements of two neuronal proteins in these organoids will demonstrate how successful the bioengineered niche will be at restoring neurogenesis to aged neural stem cells. This work could show how much of age-related cognitive decline is driven by the surrounding niche rather than intrinsic issues with the cells. Additionally, a successful organoid would also be exceptionally useful for disease modeling and for modeling strategies to restore neurogenesis in the aging brain.