PENG, T. | bioRxiv Science

bioRxiv2022

Gli2 and Gli3 Regulate Horizontal Basal Cell-Mediated Regeneration of the Olfactory Epithelium

The olfactory epithelium (OE) is a specialized neuroepithelium that is replenished by two stem cell populations: globose basal cells (GBCs) and horizontal basal cells (HBCs). Previous work indicated that HBCs contain primary cilia, organelles that mediate Hedgehog (HH) pathway activity. However, a role for HH signaling in HBCs has not been investigated. We find that GLI2 and GLI3, transcriptional effectors of the HH pathway, are expressed in HBCs in the adult OE and that their expression expands following injury. Further, Gli2-expressing descendants contribute to all major OE cell types during OE regeneration. HBC-specific expression of constitutively active GLI2 drives inappropriate HBC proliferation, alters HBC identity, and culminates in a failure of HBCs to differentiate into olfactory sensory neurons (OSNs) following injury. HBC- specific deletion of endogenous Gli2 and Gli3 results in decreased HBCs and OSNs following OE injury. These data identify GLI2 and GLI3 as key regulators of HBC-mediated OE regeneration.

cell biology↗

bioRxiv2020

Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung

Senescent cells are recognized drivers of aging-related decline in organ function, but deciphering the biology of senescence in vivo has been hindered by the paucity of tools to track and isolate senescent cells in tissues1-4. Deleting senescent cells from transgenic murine models have demonstrated therapeutic benefits in numerous age-related diseases5-11, but the identity, behavior, and function of the senescent cells deleted in vivo remain elusive. We engineered an ultra-sensitive reporter of p16INK4a, a biomarker of senescence12, to isolate and track p16INK4a+ cells in vivo. Surprisingly, p16INK4a+ mesenchymal cells appear in the basement membrane adjacent to epithelial progenitors in the lung shortly after birth, and these cells demonstrate senescent characteristics in vivo and ex vivo. Transcriptomic analysis of p16INK4a+ mesenchymal cells from non-aged lungs demonstrates a transition to a secretory phenotype upon airway epithelial injury. Heterotypic 3D organoid assays show that injured p16INK4a+ mesenchymal cells enhance epithelial progenitor proliferation, and we identified EREG as a novel airway progenitor mitogen produced by the secretory p16INK4a+ mesenchymal cells. Mesenchymal-specific deletion of the p16INK4a gene abrogates features of senescence in vivo, but also attenuates normal epithelial repair. Thus, p16INK4a+ mesenchymal cells can act as sentinels for the airway epithelial stem cell niche, poised to transition to a senescence-associated secretory phenotype to support barrier repair. Our data identify possible cellular targets in vivo for a rapidly growing list of senolytic therapies, but also raises important questions about the hidden cost of targeting senescent cells present in normal organs.

cell biology↗