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Symmetrically fated progenitors dynamically accommodate tissue maintenance in the esophagus [scRNA-seq]

ABSTRACT: Progenitor cells adapt their behavior in response to tissue demands. However, the molecular mechanisms controlling esophageal progenitor decisions remain largely unknown. Here we demonstrate the presence of a Troy(Tnfrsf19)-expressing progenitor subpopulation localized to defined regions along the esophageal axis. Lineage tracing and mathematical modelling demonstrate that Troy-positive progenitor cells are prone to undergoing symmetrical fate choices and contribute to esophageal tissue homeostasis long-term. Functionally, TROY inhibits progenitor proliferation and enables commitment to differentiation without affecting fate symmetry. Whereas Troy expression is stable during esophageal homeostasis, progenitor cells downregulate Troy in response to tissue stress, enabling proliferative expansion of basal cells refractory to differentiation and reestablishment of tissue homeostasis. Our results demonstrate functional, spatially restricted, progenitor heterogeneity in the esophageal epithelium and unveil how dynamic regulation of Troy coordinates tissue generation.

ORGANISM(S): Mus musculus

PROVIDER: GSE255402 | GEO | 2024/03/07

REPOSITORIES: GEO

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Symmetrically fated progenitors dynamically accommodate tissue maintenance in the esophagus [RNA-seq]

Project description:Progenitor cells adapt their behavior in response to tissue demands. However, the molecular mechanisms controlling esophageal progenitor decisions remain largely unknown. Here we demonstrate the presence of a Troy(Tnfrsf19)-expressing progenitor subpopulation localized to defined regions along the esophageal axis. Lineage tracing and mathematical modelling demonstrate that Troy-positive progenitor cells are prone to undergoing symmetrical fate choices and contribute to esophageal tissue homeostasis long-term. Functionally, TROY inhibits progenitor proliferation and enables commitment to differentiation without affecting fate symmetry. Whereas Troy expression is stable during esophageal homeostasis, progenitor cells downregulate Troy in response to tissue stress, enabling proliferative expansion of basal cells refractory to differentiation and reestablishment of tissue homeostasis. Our results demonstrate functional, spatially restricted, progenitor heterogeneity in the esophageal epithelium and unveil how dynamic regulation of Troy coordinates tissue generation.

2024-03-07 | GSE255401 | GEO

Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

Project description:The adult mouse subependymal zone (SEZ) provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem cell number within a shared niche fluctuates over time. Fate-mapping proliferating cells using a novel Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a novel niche-based mechanism for the regulation of NSC fate and number.

2018-01-12 | GSE65970 | GEO

Expression profiling of Troy positive gastric cells

Project description:Proliferation of the self-renewing epithelium of the gastric corpus occurs almost exclusively in the isthmus of the glands, from where cells migrate bi-directionally towards pit and base. The isthmus is therefore generally viewed as the stem cell zone. We find that the stem cell marker Troy is expressed at the gland base by a small subpopulation of chief cells. By lineage tracing using a Troy-eGFP-ires-CreERT2 allele, single marked cells are shown to generate entirely labeled gastric units over periods of months. This phenomenon accelerates upon tissue damage. Troy+ chief cells can be cultured to generate long-lived gastric organoids. Troy marks a specific, 'plastic' subset of differentiated chief cells capable of replenishing entire gastric units, essentially serving as a quiescent ‘reserve’ stem cell. An EGFP-ires-CreERT2 cassette was introduced into the transcriptional start side of Tnfrsf19 (Troy), resulting in the expression of EGFP and CreERT2 under the control of endogenous Troy-regulatory sequences. Troy is expressed in basally located chief and parietal cells. Using FACS, Troy positive chief and parietal cells can be isolated separately. Expression profiling was performed on these two cell types: three arrays of sorted chief cells, two arrays of sorted parietal cells. As a reference, two arrays of separately isolated whole gastric corpus glands were added. In addition, single sorted Troy positive chief cells can be placed in culture, forming 3D cultures called organoids. Three arrays were generated from different organoid cultures, one time in normal medium containing the factors EGF, Gastrin, FGF10, Noggin, Wnt3a and Rspondin (EGFNWR medium) and one time in medium containing only EGF and Rspondin (ER medium).

2013-10-23 | E-GEOD-44060 | biostudies-arrayexpress

Death Receptors DR6 and TROY Regulate Brain Vascular Development

Project description:Signaling events that regulate central nervous system (CNS) angiogenesis and blood-brain barrier (BBB) formation are only beginning to be elucidated. By evaluating the gene expression profile of mouse vasculature, we identified DR6/TNFRSF21 and TROY/TNFRSF19 as regulators of CNS-specific angiogenesis in both zebrafish and mice. Furthermore, these two death receptors interact both genetically and physically and are required for vascular endothelial growth factor (VEGF)-mediated JNK activation and subsequent human brain endothelial sprouting in vitro. Increasing beta-catenin levels in brain endothelium upregulate DR6 and TROY, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for BBB development. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. 5 replicates of 3 time points for either brain or liver/lung facs sorted vascaulture. One adult liver/lung replicate was not used as it failed QC

2012-02-15 | E-GEOD-35802 | biostudies-arrayexpress

Death Receptors DR6 and TROY Regulate Brain Vascular Development

2012-02-15 | GSE35802 | GEO

Troy/Tnfrsf19 marks epidermal cells that govern interfollicular epidermal renewal and cornification

Project description:Troy/Tnfrsf19 marks epidermal cells that govern interfollicular epidermal renewal and cornification

| PRJNA694196 | ENA

Troy/Tnfrsf19 marks epidermal cells that govern interfollicular epidermal renewal and cornification

Project description:The skin epidermis is a highly compartmentalised tissue consisting of a cornifying epithelium called the interfollicular epidermis (IFE) and associated hair follicles (HFs). Several stem cell populations have been described that mark specific sub compartments in the skin but none of them is IFE-specific. Here we identify Troy as a marker of IFE and HF infundibulum basal layer cells in embryonic and adult human and mouse epidermis. Genetic lineage-tracing experiments demonstrate that Troy-expressing basal cells contribute to long-term renewal of all layers of the cornifying epithelium. Single-cell transcriptomics and organoid assays of Troy-expressing cells as well as their progeny confirmed stem cell identity as well as the ability to generate differentiating daughter cells. In conclusion, we define Troy as a marker of epidermal basal cells that govern interfollicular epidermal renewal and cornification.

2021-08-05 | GSE165379 | GEO

Metabolomic Profiling of Human Pluripotent Stem Cell Differentiation into Lung Progenitors

Project description:Metabolism is vital to cellular function and tissue homeostasis during human lung development. In utero, embryonic pluripotent stem cells undergo endodermal differentiation towards a lung progenitor cell fate that can be mimicked in vitro using induced human pluripotent stem cells (hiPSCs) to study genetic mutations. To identify differences between wild type and surfactant protein B (SFTPB)-deficient cell lines during endoderm specification towards lung, we used an untargeted metabolomics approach to evaluate the developmental changes in metabolites. We found that the metabolites most enriched during the differentiation from pluripotent stem cell to lung progenitor cell, regardless of cell line, were sphingomyelins and phosphatidylcholines, two important lipid classes in fetal lung development. The SFTPB mutation had no metabolic impact on early endodermal lung development. The identified metabolite signatures during lung progenitor cell differentiation may be utilized as biomarkers for normal embryonic lung development.

2021-06-29 | ST002055 | MetabolomicsWorkbench

Fibrogenic cell plasticity blunts tissue regeneration and aggravates muscular dystrophy

Project description:Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular Dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered-tracing mice, we demonstrate that in dystrophic muscle, specialized cells of muscular, endothelial and hematopoietic origins gain plasticity towards a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity was also observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component. TGFb exposure induced gene expression was measured after 4 days of treatment compared to untreated cells. Three independent experiments were performed both for the treatment and for the control

2015-04-09 | E-GEOD-67687 | biostudies-arrayexpress

Single cell RNA-sequencing of esophageal epithelium from wild type and p63-KO mice

Project description:Cell fate determination and maintenance play critical roles in establishing and preserving tissue identity and function during organ development. Aberrant cell fate transitions can lead to cancer cells acquiring lineage plasticity, resulting in tumor heterogeneity and resistance to treatment. Trp63 (p63) is a transcription factor important for the formation of stratified squamous epithelium in the esophagus. Here, we report an unexpected role of p63 in protecting esophageal basal progenitor cells from committing to a neuroendocrine fate. Combination of single cell RNA sequencing analysis, lineage tracing and in vitro differentiation, we found that deletion of p63 in developing murine esophagus and in human embryonic stem cells results in extensive differentiation towards neuroendocrine lineage.

2024-07-25 | GSE263694 | GEO

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