期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：E5068-E5077
DOI：10.1073/pnas.1512272112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceHarnessing the inherent capability of stem cells to maintain and regenerate injured tissues is a prerequisite for their use in mending damage to the nervous system. In the olfactory epithelium stem cells accomplish neurogenesis and epithelial repair throughout life to an extent not seen elsewhere in the nervous system. Here we show that the transcription factor protein 63 (p63) is a master regulator of the transition from the reserve to the active stem cell pool in the epithelium. Loss of p63 expression in reserve basal cells is necessary and sufficient for activation, without compromising stem cell status. Identification of this central mechanism provides a target for stem cell activation in this uniquely accessible source of patient-specific, neurogenic stem cells. Adult tissue stem cells can serve two broad functions: to participate actively in the maintenance and regeneration of a tissue or to wait in reserve and participate only when activated from a dormant state. The adult olfactory epithelium, a site for ongoing, life-long, robust neurogenesis, contains both of these functional stem cell types. Globose basal cells (GBCs) act as the active stem cell population and can give rise to all the differentiated cells found in the normal tissue. Horizontal basal cells (HBCs) act as reserve stem cells and remain dormant unless activated by tissue injury. Here we show that HBC activation following injury by the olfactotoxic gas methyl bromide is coincident with the down-regulation of protein 63 (p63) but anticipates HBC proliferation. Gain- and loss-of-function studies show that this down-regulation of p63 is necessary and sufficient for HBC activation. Moreover, activated HBCs give rise to GBCs that persist for months and continue to act as bona fide stem cells by participating in tissue maintenance and regeneration over the long term. Our analysis provides mechanistic insight into the dynamics between tissue stem cell subtypes and demonstrates that p63 regulates the reserve state but not the stem cell status of HBCs.
