Endogenous stem cells for enhancing cognition in the diseased brain.

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Adult neural progenitor cells or neural stem cells (NSCs) persist in the adult human brain in two well-established regions, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus. Newborn neurons have been observed in the human SGZ in adults and contribute to specific forms of memory encoding at least in rodents (Braun and Jessberger, 2014). Neurogenesis from the adult SVZ was primarily identified in the olfactory bulb in rodents and was shown to stop early in life in humans despite the continuous presence of NSCs (Sanai et al., 2011). However, a recent study reports neurogenesis in the striatum from the adult human SVZ (Ernst et al., 2014). This finding highlights the difference between rodents and humans and the fact that some brain regions display an unexpected capacity for newborn neuron migration and survival. The SVZ is a prime region to consider for brain repair considering that it spans the entire cerebrum while the SGZ is limited to the hippocampus. Other regions are now known to contain NSCs or progenitor cells such as the hypothalamus, but this will not be discussed here. Several milestones need to be achieved prior to considering functional repair. These include, but may not be limited to: (1) Understanding the mechanisms leading to NSC quiescence and loss with aging. Several mechanisms are involved in the different regulatory steps of NSC self-renewal and loss. We will emphasize some of the mechanisms leading to NSC loss with aging. Once these mechanisms are identified, we should be able to amplify the pool of NSCs and direct their differentiation. (2) Identifying the molecules responsible for fate determination of NSCs and their daughter cells to generate glia or neurons of different types, including interneurons and long projection neurons. (3) Determining the inhibitory molecules that make the adult brain resistant to repair. Some repair has been reported in the cortex of rodents, but it is abortive possibly due to an unfriendly environment. (4) Finally, although we can genetically manipulate NSCs in rodents, it is a different issue in humans. Delivery systems need to be improved. Each of this point is further discussed below.