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An in vitro model of acute horizontal basal cell activation reveals dynamic gene regulatory networks underlying the acute activation phase

ABSTRACT: Unlike most of the adult nervous system, the olfactory epithelium (OE) can regenerate neurons lost during normal homeostasis or after injury. This life-long regeneration is propagated by two populations of stem cells, the actively proliferating globose basal cells (GBCs) and the dormant horizontal basal cells (HBCs). HBCs only activate and contribute to epithelial regeneration in the context of severe injury, and this activation is mediated by the loss of the transcription factor Tp63. While the HBC differentiation trajectories that occur after activation have been described with lineage tracing and single-cell RNA seq experiments, the immediate consequences of injury on HBC gene expression and fate commitment have not been explored. We present an in vitro model of the acute activation process for HBCs in response to treatment with phorbol 12-myristate 13-acetate (PMA) to explore the molecular underpinnings of these early activation events. We find that treating HBCs with PMA induces the rapid degradation of TP63, and we find that this effect is partially reversed when cells are allowed to recover in maintenance media. Using bulk RNA sequencing we found that PMA-treated HBCs pass through various stages of acute activation identifiable by specific gene regulatory signatures. These transcriptomic phases are associated with varying degrees of plasticity with regards to activated HBCs ability to engraft in transplant models.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE215797 | GEO | 2024/06/24

REPOSITORIES: GEO

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Project description:Ongoing, lifelong neurogenesis maintains the neuronal population of the olfactory epithelium in the face of piecemeal neuronal turnover and restores it following wholesale loss. The molecular phenotypes corresponding to different stages along the progression from multipotent globose basal cell (GBC) progenitor to differentiated olfactory sensory neuron are poorly characterized. We used the transgenic expression of GFP and cell surface markers to FACS-isolate Sox2-GFP(+) GBCs, Neurog1-GFP(+) GBCs and immature neurons, and OMP-GFP(+) mature neurons from normal adult mice. In addition, the latter two populations were also collected 3 weeks after olfactory bulb ablation, a lesion that results in persistently elevated neurogenesis. Global profiling of mRNA from the populations indicates that all stages of neurogenesis share a cohort of >2100 genes that are upregulated compared to sustentacular cells. A further cohort of >1200 genes are specifically upregulated in GBCs as compared to sustentacular cells and differentiated neurons. The increased rate of neurogenesis caused by olfactory bulbectomy had little effect on the transcriptional profile of the Neurog1-GFP(+) population. In contrast, the abbreviated lifespan of OMP-GFP(+) neurons born in the absence of the bulb correlated with substantial differences in gene expression as compared to the mature neurons of the normal epithelium. Detailed examination of the specific genes upregulated in the different progenitor populations revealed that the chromatin modifying complex proteins LSD1 and coREST were expressed sequentially in upstream Sox2-GFP(+) GBCs and Neurog1-GFP(+) GBCs/immature neurons. The expression patterns of these proteins are dynamically regulated after activation of the epithelium by methyl bromide lesion. Total RNA was isolated from dissected, dissociated and FACS-purified olfactory mucosal cells from normal adult mice or mice 3 weeks after unilateral bulbectomy. Cells were purified with FACS using endogenous GFP fluorescence from various transgenic lines and cell surface labeling. Two to seven adult mice were used per replicate and three replicates per condition were performed using Illumina bead arrays. 21 samples from olfactory mucosa were analyzed in this series and 3 samples were from a commercially available reference RNA sample. Universal mouse reference RNA from Stratagene was used as a general control and Normal olfactory mucosa was used as a tissue specific control.

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An in vitro model of acute horizontal basal cell activation reveals dynamic gene regulatory networks underlying the acute activation phase

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