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E-GEOD-62741

ABSTRACT: Thymic T-cell progenitor development is supported by membrane bound Kit ligand provided by a combined vascular endothelial and epithelial niche.

OTHER RELATED OMICS DATASETS IN: PRJNA265043

PROVIDER: E-GEOD-62741 | ExpressionAtlas | 2019-05-14

REPOSITORIES: ExpressionAtlas

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			Action	DRS
	E-GEOD-62741-analysis-methods.tsv	Tabular
	E-GEOD-62741-analytics.tsv	Tabular
	E-GEOD-62741-analytics.tsv.undecorated	Tabular
	E-GEOD-62741-analytics.tsv.undecorated.unrounded	Tabular
	E-GEOD-62741-analytics.tsv.unrounded	Tabular

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Mus musculus

Project description:Thymic T-cell progenitor development is supported by membrane bound Kit ligand provided by a combined vascular endothelial and epithelial niche.

| PRJNA265043 | ENA

Bi-directional signaling by membrane-bound KitL induces proliferation and co-ordinates thymic endothelial cell and thymocyte expansion

Project description:The ligand for the c-Kit receptor, KitL, exists as a membrane-associated (mKitL) and a soluble form (sKitL). KitL functions outside c-Kit activation have not been identified. We show that co-culture of c-Kit– and mKitL–expressing NIH3T3 cells results in signaling through mKitL: c-Kit–bound mKitL recruits calcium-modulating cyclophilin ligand (CAML) to selectively activate Akt, leading to CREB phosphorylation, mTOR pathway activation, and increased cell proliferation. Activation of mKitL in thymic vascular endothelial cells (VECs) induces mKitL- and Akt-dependent proliferation, and genetic ablation of mKitL in thymic VECs blocks their c-Kit responsiveness and proliferation during neonatal thymic expansion. Therefore, mKitL–c-Kit form a bi-directional signaling complex that acts in the developing thymus to coordinate thymic VEC and early thymic progenitor (ETP) expansion by simultaneously promoting ETP survival and VEC proliferation. This mechanism may be relevant to both normal tissues and malignant tumors that depend on KitL–c-Kit signaling for their proliferation.

2018-11-21 | PXD011061 | Pride

Thymic T-cell progenitor development is supported by membrane bound Kit ligand provided by a combined vascular endothelial and epithelial niche.

Project description:Gene expression analysis of purified KitL-tomato+ and KitL-tomato- thymic vascular endothelial cells, cortical and medullary thymic epithelial cells from 5 weeks old male kitL-tomato reporter mice Differentially expressed genes analysis of thymic stromal cells

2016-01-18 | E-GEOD-62741 | biostudies-arrayexpress

Thymic T-cell progenitor development is supported by membrane bound Kit ligand provided by a combined vascular endothelial and epithelial niche.

2016-01-18 | GSE62741 | GEO

RNA-seq on cells with or without pathogenic PAX1 variants at different stages of in vitro differentiation into thymic epithelial progenitor cells

Project description:Bi-allelic, loss-of-function PAX1 variants underlie a syndromic form of severe combined immunodeficiency (SCID) by disrupting thymus development. To assess if bi-allelic PAX1 variants affect differentiation of thymic epithelial cells in vitro, we reprogrammed fibroblasts from a healthy control and two patients with bi-allelic pathogenic PAX1 variants to induced pluripotent stem cells (iPSCs), and subsequently differentiated these to thymic epithelial progenitor cells (TEP).

2020-02-15 | GSE138784 | GEO

mRNA-seq of mouse lung vascular endothelial cells and mouse liver sinusoidal endothelial cells before and after their partial reprogramming into progenitor-like cells and recellularization of decellularized mouse lung scaffolds

Project description:In this study we developed highly proliferative and lineage restricted lung endothelial derived progenitor-like cells using the transient expression of Yamanaka factors via doxycycline inducible system combined with LIF-supplemented media. We investigate the potential of these induced progenitor-like cells for the vascular engineering of the lungs. Our results show that these cells recapitulate the segment specific heterogeneity in the decellularized lung scaffolds and show immediate recovery of endothelial genes after recellularization.

2020-06-23 | E-MTAB-8394 | biostudies-arrayexpress

Single-cell RNA sequencing of thymic EC and TEC from control and RANKL treated aged mice

Project description:Age-related thymic involution, leading to reduced T cell production, is one of the major causes of immunosenescence. This results in an increased susceptibility to cancers, infections, and autoimmunity and in reduced vaccine efficacy. Here, we identified that the receptor activator of nuclear factor κB (RANK)-RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.

2024-09-30 | GSE241880 | GEO

Developmental dynamics of two bipotent progenitors of thymic epithelium

Project description:T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. Compared to other organs, the size and cellular composition of the thymus is unusually dynamic, exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naïve T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved. Here, we combine scRNA-seq and a novel CRISPR/Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bi-potent progenitor type biased towards cortical epithelium, and a postnatal bi-potent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.

2022-03-30 | GSE106856 | GEO

Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema

Project description:Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. We have demonstrated that paladin has a predominant vascular expression pattern and shifts from endothelial to mural cells during mouse development. We have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice displayed an emphysema-like phenotype with increased alveolar air spaces and impaired lung function with obstructive changes. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that paladin is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis. Proteomic analysis of Pald1 wild type and knock-out mice reveal that most of the protein expression differences are related to sex and not genotype, supporting the notion that sex can be a major factor for lung development and disease. In addition, Pald1 wild type and knock-out mice exhibit differential expression of HPGD, hydroxyprostaglandin dehydrogenase 15 (NAD), the major enzyme for degradation of prostaglandins.

2017-11-01 | PXD005625 | JPOST Repository

Thymic epithelial organoids mediate T cell development [scRNA-seq]

Project description:Although the advent of organoids opened unprecedented perspectives for basic and translational research, immune system-related organoids remain largely underdeveloped. Here we established organoids from the thymus, the lymphoid organ responsible for T cell development. We identified conditions enabling thymic epithelial progenitor cell proliferation and development into organoids with diverse cell populations and transcriptional profiles resembling in vivo thymic epithelial cells (TECs) more closely than traditional TEC cultures. Contrary to these two-dimensional cultures, thymic epithelial organoids maintained thymus functionality in vitro and mediated physiological T cell development upon reaggregation with T cell progenitors. The reaggregates showed in vivo-like epithelial diversity and ability to attract T cell progenitors. Thymic epithelial organoids are the first organoids originating from the stromal compartment of a lymphoid organ. They provide new opportunities to study TEC biology and T cell development in vitro, paving the way for future thymic regeneration strategies in ageing or acute injuries.

2024-07-16 | GSE240697 | GEO

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