UC Berkeley

Stroke, Alzheimer's Disease, and other neurological pathologies are not only among the leading causes of death in the United States but also account for a huge portion of national healthcare expenditure (National Center for Health Statistics, 2016 report). Advancing our understanding of the bodily response to neural injury and the mechanisms that might be used to prevent or heal that injury is of paramount importance. This dissertation is a presentation of work aimed at understanding the molecular cascades that govern regeneration after neural injury using the olfactory neuroepithelium (OE) - one of the few locations in the adult where such regeneration is naturally able to occur - as a model.

Throughout the human lifespan, the OE is continually subject to chemotoxic and mechanical insult. Remarkably, the epithelium has the ability to fully regenerate all cell types, both neurons and supporting cells after minor or extensive injury. Understanding the biological regulation that allows for this regeneration serves two purposes: One, these mechanisms may be usefully employed in the development of translational methods for treating neurological diseases. Two, the cells and stem cells of the OE constitute a rich potential source of cells for possible transplantation in translational approaches to pathologies where neural death has occurred. In this dissertation, we evaluated the functional importance of the Stem Cell Factor growth factor (SCF) and C-Kit, the receptor tyrosine kinase SCF binds to, in neural regeneration.

The regenerative capability of the human epithelium is faithfully recapitulated by the murine OE, making it an ideal model of the human system for use in researching regenerative mechanisms. Using transgenic mouse models, we examined the expression of SCF and C-Kit in the OE via a combination of molecular imaging and single-cell transcriptional sequencing, and we discovered that SCF is expressed by all sustentacular (SUS) supporting cells and all horizontal basal stem cells, both in the uninjured and in the injured/regenerating OE. C-Kit is expressed by a large fraction of the globose basal cells, a population which is heterogeneous and consists both of stem and committed progenitor cells, and some microvillous cells, a population which is the subject of much current research. Interestingly, during regeneration after experimentally induced injury, the majority of cells express SCF or C-Kit. These striking expression patterns led us to look for deficits in SCF knock-out transgenic mice with the hope of better understanding the function of this growth factor. We found that SCF is critical to production of normal numbers of neurons and microvillous cells during regeneration. Extensive assessment of the expression patterns and impact of the ablation of SCF function in the OE led us to a novel understanding of the role of this growth factor/receptor pair in neural recovery after injury: SCF is critical for OE stem cells to make neuronal fate decisions during regeneration from injury.