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LTβR controls thymic portal endothelial cells for hematopoietic progenitor cell homing and T cell regeneration

ABSTRACT: Continuous thymic homing of hematopoietic progenitor cells (HPCs) via the blood is critical for normal T cell development. However, the nature and the differentiation program of the specialized thymic endothelial cells (ECs) controlling this process remain poorly understood. Here, using conditional gene-deficient mice, we find that lymphotoxin beta receptor (LTβR) directly controls thymic ECs to guide HPC homing. Interestingly, T cell deficiency or conditional ablation of T-cell-engaged LTβR signaling results in a defect in thymic HPC homing, suggesting the feedback regulation of thymic progenitor homing by thymic products. Furthermore, we identify and characterize a special thymic portal EC population with features that guide HPC homing. LTβR is essential for the differentiation and homeostasis of these thymic portal ECs. Finally, we show that LTβR is required for T cell regeneration upon irradiation-induced thymic injury. Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing.

ORGANISM(S): Mus musculus

PROVIDER: GSE83114 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA324805

REPOSITORIES: GEO

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Mus musculus

Project description:LTβR controls thymic portal endothelial cells for hematopoietic progenitor cell homing and T cell regeneration

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Stimulation of LTβR on human fibroblasts

Project description:LTβR signaling is crucial for immune development, homeostasis, and inflammation. To identify new factors that influence the quality of LTβR function, we combined transcriptomics with WGCNA.

2020-03-07 | GSE146536 | GEO

Inhibition of LTβR-signalling blocks epithelial apoptosis and activates endogenous Wnt-induced regeneration

Project description:Lymphotoxin β-receptor-signalling orchestrates lymphoid neogenesis and subsequent tertiary lymphoid structures (TLS) associated with severe chronic inflammatory diseases spanning multiple organ systems. How LTβR-signalling drives chronic tissue damage particularly in the lung, which mechanism(s) regulate this process, and whether LTβR-blockade might be of therapeutic value has remained unclear. Here we demonstrate increased lymphotoxin expression of LTbR-ligands on myeloid and adaptive and innate immune-cells, enhanced non-canonical NF-κB signalling and enrichment of LTβR-target gene expression in epithelial cells of lungs from patients and mice with smoking-associated chronic obstructive pulmonary disease (COPD). Accordingly, Therapeutic inhibition of LTβR-signalling in young and aged mice with COPD disrupted TLS, reverted lung tissue destruction, airway-fibrosis and systemic muscle wasting. Mechanistically, we identified that LTβR-signalling blockade leads to diminished cell-death, concomitantly reactivated endogenous Wnt/β-catenin-signalling in alveolar epithelial cells and reduced TGFβ-signalling in airways. These findings highlight LTβR as a viable therapeutic target against TLS induced tissue damage that translates into novel anti-inflammatory, regenerative strategies to treat COPD.

2020-07-10 | GSE125521 | GEO

Analysis of lung transcriptomic changes following inhibition of LTβR-signalling in cigarette smoke exposed mice

Project description:How LTβR-signalling drives chronic tissue damage particularly in the lung, which mechanisms regulate this process, and whether LTβR-blockade might be of therapeutic value has remained unclear. To study the mechanisms underlying LTβR-inhibition, a transcriptional analysis was performed on lung tissue from B6 mice exposed to cigarette smoke for 6 months and treated therapeutically with LTβR-Ig from 4 to 6 months compared to mice exposed to cigarette smoke for 6 months and treated with control Ig from 4 to 6 months and filtered air control. Single-cell RNA-Seq identified 24 distinct cell populations across >20,000 cells in lungs with distinct changes occurring upon cigarette smoke exposure and LTβR-Ig treatment.

2020-07-10 | GSE151674 | GEO

Type 3 innate lymphoid cells direct goblet cell differentiation via the LT-LTβR pathway during Listeria infection

Project description:As a specialized subset of intestinal epithelial cells (IECs), goblet cells (GCs) play an important role during the antibacterial response via mucin production. However, the regulatory mechanisms involved in GC differentiation and function during infection, particularly the role of immune cell-IEC crosstalk, remain largely unknown. Here, using VillinΔLtbr conditional knockout mice, we demonstrate that LTβR, expressed on IECs, is required for GC hyperplasia and mucin 2 (MUC2) expression during Listeria infection for host defense but not homeostatic maintenance in the naïve state. Analysis of single gene-deficient mice revealed that the ligand lymphotoxin (LT) but not LIGHT and type 3 innate lymphoid cells (ILC3s) but not conventional T cells are required for MUC2-dependent Listeria control. Conditional deficiency of LT in ILC3s further confirmed the importance of LT signals derived from ILC3s. Lack of ILC3-derived LT or IEC-derived LTβR resulted in defective expression of genes related to GC differentiation but was not correlated with IEC proliferation and cell death, which were found to be normal by Ki-67 and Annexin V staining. In addition, the alternative NF-κB signaling pathway (involving RelB) in IECs was found to be required for the expression of GC differentiation-related genes and Muc2 and required for the anti-Listeria response. Therefore, our data together suggest a previously unrecognized ILC3-IEC interaction and LT-LTβR-RelB signaling axis governing GC differentiation and function during Listeria infection for host defense.

2020-05-26 | GSE150071 | GEO

Stimulation of LTβR on human fibroblasts

Project description:Stimulation of LTβR on human fibroblasts

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GATA2/eGFP knockin study to trace the endothelial to hematopoietic transition and hematopoietic progenitor cells in human hematopoiesis.

Project description:We generated GATA2/eGFP knockin human embryonic stem cells (H1-GATA2W/eGFP hESCs) and analyzed eGFP expression at different hematopoietic stages, paritcularly the hemogenic endothelium (HE) and hematopoietic progenitor cell (HPC) stage. Our results revealed that, at the HE stage, eGFP expression discriminates authentic HE from non-hematopoietic endothlial cells (EC) and, at the HPC stage, eGFP expression marks the HPC. Further transcriptome comparison analysis revealed distinct characteristics of the HE and EC. Our study provided ideal model to study the EHT and HPC generation, therefore underpining further study on human ESC modeled hematopoiesis.

2017-02-08 | GSE74041 | GEO

A single cell transcriptome atlas of murine endothelial cells

Project description:The heterogeneity of endothelial cells (ECs), lining blood vessels, across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomic data from 11 tissues of the model organism Mus musculus. We propose a new classification of EC phenotypes based on transcriptome signatures and inferred putative biological features. We identified top-ranking markers for ECs from each tissue. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) resembled each other across tissues, but only arterial, venous and lymphatic (not capillary) ECs shared markers, illustrating a greater heterogeneity of capillary ECs. We identified high-endothelial-venule and lacteal-like ECs in the intestines, and angiogenic ECs in healthy tissues. Metabolic transcriptomes of ECs differed amongst spleen, lung, liver, brain and testis, while being similar for kidney, heart, muscle and intestines. Within tissues, metabolic gene expression was heterogeneous amongst ECs from different vascular beds, altogether highlighting large EC heterogeneity.

2020-02-13 | E-MTAB-8077 | biostudies-arrayexpress

Endothelial cell heterogeneity in pathological angiogenesis characterized by metabolic transcriptome diversity

Project description:Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcrip-tomes. Here, by scRNA-sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference of CNV-ECs revealed that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. EC phenotypes displayed metabolic transcriptome heterogeneity. Hypothesizing that conserved genes are more important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome scale metabolic modeling, and gene expression me-ta-analysis in multiple cross-species datasets, followed by functional validation, to identify the top-ranking metabolic targets SQLE and ALDH18A1, involved in EC proliferation and collagen production, respectively, as novel angiogenic targets.

2020-03-31 | E-MTAB-8604 | biostudies-arrayexpress

Characterization of organ-level specification of murine vascular endothelial cells from embryonic-stage to post-puberty adulthood.

Project description:Vascular endothelial cells (ECs) establish via paracrine signaling tissue-specific niches that promote organ revascularization and regeneration. Given these executive functions, transplantation of ECs into the vasculature has been used to stimulate organ repair. However, challenges in faithfully deriving tissue-specific endothelium within in vitro culture conditions limit large-scale expansion potential, long-term functional stability, and the cell homing and engraftment potential towards the target organ. Identification of the transcriptional regulators that modulate the specification of generic or unspecified endothelial cell populations into tissue-specific vascular ECs may provide novel factors to be incorporated into standard stem-cell differentiation protocols. Such controlled expression of the appropriate angiocrine factors—in combination with the niche microenvironment—could support the necessary crosstalk and cell-to-cell membrane interactions necessary for positioning and anastomosis when transplanted. Previously, investigation of the transcriptome profiles of ECs originating from diverse vascular beds has helped identify potential transcriptional regulators and gene markers of EC tissue specification. We aim to expand on these studies by elaborating on the progression of EC tissue specification as it occurs from embryonic development to adulthood. A better understanding of how ECs acquire their tissue specificity and deconvolution of the transient expression patterns of key molecular regulators could provide crucial information on the establishment of EC tissue-specific function which can then be recapitulated in vitro. Our long-term goal is to generate transcriptionally stable and functional tissue-specific ECs from stem-cell derived EC banks suitable for transplantation for the purpose of promoting non-fibrotic tissue regeneration after organ injury.

2019-09-20 | GSE129005 | GEO

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