Notch Signaling Regulates Lgr5+ Olfactory Epithelium Progenitor/Stem Cell Turnover and Mediates Recovery of Lesioned Olfactory Epithelium in Mouse Model

Abstract

The Notch signaling pathway regulates stem cell proliferation and differentiation in multiple tissues and organs, and is required for tissue maintenance. However, the role of Notch in regulation of olfactory epithelium (OE) progenitor/stem cells to maintain tissue function is still not clear. A recent study reported that leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is expressed in globose basal cells (GBCs) localized in OE. Through lineage tracing in vivo, we found that Lgr5 cells act as progenitor/stem cells in OE. The generation of daughter cells from Lgr5 progenitor/stem cells is delicately regulated by the Notch signaling pathway, which not only controls the proliferation of Lgr5 cells and their immediate progenies but also affects their subsequent terminal differentiation. In conditionally cultured OE organoids in vitro, inhibition of Notch signaling promotes neuronal differentiation. Besides, OE lesion through methimazole administration in mice induces generation of more Notch1 cells in the horizontal basal cell (HBC) layer, and organoids derived from lesioned OE possesses more proliferative Notch1 HBCs. In summary, we concluded that Notch signaling regulates Lgr5 GBCs by controlling cellular proliferation and differentiation as well as maintaining epithelial cell homeostasis in normal OE. Meanwhile, Notch1 also marks HBCs in lesioned OE and Notch1 HBCs are transiently present in OE after injury. This implies that Notch1 cells in OE may have dual roles, functioning as GBCs in early development of OE and HBCs in restoring the lesioned OE. Stem Cells 2018;36:1259-1272.

Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway

“…Aging attenuated the recruitment of Lgr5+ cells in injured OE. Previous work reported that Lgr5 marked GBCs in the OE (Chen et al, 2014) and Lgr5+/Notch1+ cells participated in the OE regeneration postinjury (Dai et al, 2018). Based on these findings, here, we showed that aging altered the stemness of Lgr5+ cells in injured OE, keeping more Lgr5+ cells in dormancy.…”

“…Notch signaling is necessary to direct the neuronal differentiation in the OE regeneration (Herrick et al, 2018), and Notch1 is required to maintain dormancy of reserve HBCs (Herrick et al, 2017). Our previous work indicated that Notch1 activation enhanced the proliferation in leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive progenitor cells and regulated the generation of mature sensory neurons in the OE (Dai et al, 2018). Thus, it is of interest to elucidate whether the effect of aging on the OE regeneration will be counteracted via Notch signaling activation.…”

Pharmacologic modulation of nasal epithelium augments neural stem cell targeting of glioblastoma

“…It is also plausible to hypothesize that basal and horizontal stem-like cells rapidly replacing damaged epithelium 13 secrete soluble tropic factors to support the persistence and survival of NSCs within the nasal cavity. Dai et al showed that the NOTCH signaling hub, also important for the function of NSC pools 22-24, mediates the recovery of olfactory epithelium after MT induced injury 25. Confirmation of these mechanisms may allow for further enhancement of NSCs vitality and augment the targeted delivery of therapeutic agents to the brain.…”

Autophagy and Akt in the protective effect of erythropoietin helix B surface peptide against hepatic ischaemia/reperfusion injury in mice

“…Early studies showed that autophagy played an important role in different I/R injury 30 – 33 and increased autophagy was believed to have a beneficial effect on liver I/R injury 34 – 36 . Some features of hepatocytes were tightly dependent on autophagy 37 .…”