CXCR4 Coordinates Long-Term Olfactory Epithelial Regeneration and Cellular Stress Response After Injury

During development, the chemokine receptor CXCR4 directs axon guidance, but it is not known if CXCR4 regulates axon targeting in the adult organism as well. We utilized the remarkable feature of the olfactory epithelium to replace damaged neurons throughout life to understand the role of CXCR4 in adult neurogenesis. Through targeting Cxcr4 in horizontal basal stem cells of the olfactory epithelium, we investigated the role of CXCR4 during injury-induced neurogenesis in adult mice by a combination of RNA-seq analysis, bioinformatic methods, behavioral experiments, and microscopical approaches. Conditional knockout mice lacking Cxcr4 initially displayed enhanced regeneration after injury of the olfactory system, resulting in increased numbers of sensory neurons and enhanced sense of smell. Moreover, we found that absence of CXCR4 alters expression of axon guidance proteins. Despite accelerated early neurogenesis, loss of CXCR4 ultimately impaired the reconstruction of the dorsomedial olfactory epithelium, leading to disrupted glomerular organization and reduced avoidance responses to aversive odors. Transcriptomic analysis revealed altered stress response pathways, suggesting impaired cellular adaptation in Cxcr4-cKO mice during regenerative repair. An increased level of ER stress in horizontal basal cells led to instability of the basal lamina, respiratory metaplasia in the dorsomedial part of the olfactory epithelium, and Bowman gland regeneration failure.