Dynamic changes of nonepithelial thymic stroma during thymus organogenesis
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ABSTRACT:
PROVIDER: PRJNA686422 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13274200_1.fastq.gz | Fastqsanger.gz | |||
| SRR13274200_2.fastq.gz | Fastqsanger.gz | |||
| SRR13274300_1.fastq.gz | Fastqsanger.gz | |||
| SRR13274300_2.fastq.gz | Fastqsanger.gz | |||
| SRR13274201_1.fastq.gz | Fastqsanger.gz |
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Project description:The thymic stroma is composed of epithelial and non-epithelial cells that collectively provide separate microenvironment controlling the homing of blood-born precursors to the tissue, and their subsequent differentiation to functionally mature and correctly selected T cells. While thymic epithelial cells are well characterised for their role in thymopoiesis, a comparably comprehensive analysis of the non-epithelial thymic stroma is lacking. Here we explore at single cell resolution the complex composition and dynamic changes that occur over time in the non-epithelial stromal compartmenti. We detail across different developmental stages in human and mouse thymus tissues and in an experimental model of the most common form of human thymus hypoplasia the separate transcriptomes of mouse mesothelium, fibroblasts, neural crest cells, endothelial and vascular mural cells. The detected gene expression signatures identify novel stromal subtypes and relate their individual molecular profiles to separate differentiation trajectories and functions. Specifically, we demonstrate an abundance and unprecedented heterogeneity of diverse fibroblast subtypes that emerge at discrete developmental stages and vary in their expression of key regulatory signalling circuits and components of the extracellular matrix. Taken together, these findings highlight the dynamic complexity of the non-epithelial thymus stroma and link the cells’ specific gene expression profiles to separate instructive roles essential for normal thymus organogenesis and tissue maintenance. The study has been granted ethical approval and is publicly listed (IRAS ID 156910, CPMS 19587).
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Project description:T cell development and selection is orchestrated in the thymus by a specialized niche of diverse stromal populations. By transcriptional single cell sorting, we de novo characterize the entire stromal compartment of the thymus. We identified dozens of cell states within the thymic stroma, with thymic epithelial cells (TEC) showing the highest degree of heterogeneity. Our analysis highlights four major medullary TEC (mTEC I-IV) populations, with distinct molecular functions, epigenetic landscapes and lineage regulators. Specifically, mTEC-IV constitutes a new and highly divergent TEC lineage with molecular characteristics of the gut chemosensory epithelial tuft cells. Mice deficient of Pou2f3, a tuft cells master regulator, resulted in complete and specific depletion of mTEC-IV, without affecting other TEC populations. Overall, our study comprehensively defines all stroma cells in the thymus and identifies a new TEC lineage associated with chemosensory properties that may potentially link the adaptive immune system to environmental and neurological signals.
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Project description:The thymus is one of the most affected organs during malnutrition, exhibiting atrophy and thymocyte depletion, characteristics that are also observed in several infectious diseases. The detrimental effects of malnutrition on immune responses to pathogens have long been recognized and it is considered a main risk factor for various infectious diseases, including visceral leishmaniasis (VL). However, the thymus has been barely studied during malnutrition and Leishmania infantum infection association. Protein malnutrition modifies intrathymic communication in L. infantum infected BALB/c mice by altering the abundance of proteins secreted to the thymic interstitial fluid (IF). We identified and compared protein abundance in the thymic IF samples from BALB/c mice that were fed with control protein (14%, CP) or low protein (4%, LP) isocaloric diets, followed by infection with L. infantum. By means of a quantitative proteomics approach using iTRAQ we identified 280 proteins of which 81% were reported as secreted by exosomes and 42% were previously described as secreted by thymic epithelial cells. LP-infected (LPi) animals showed a significant decrease in exosomal proteins, suggesting that exosomal carrier system is dysregulated in malnourished animals. LPi mice also exhibited an increase in the relative abundance of proteins involved in lipid metabolism and tricarboxylic acid cycle, suggestive of a non-proliferative microenvironment. Accordingly, flow cytometry analysis revealed that protein malnutrition decreases the proliferation of single positive and double positive T cells. Proteins engaged in glycolysis, protein ubiquitination and mRNA processing were significantly decreased. In addition, a significant decrease in the abundance of galectin-1 and increase of plasminogen were observed in malnourished animals. Together, the reduced cortical area, decreased proliferation, increased abundance of lipid- and tricarboxylic acid cycle-related proteins, and altered abundance of galectin-1 and plasminogen indicate a dysfunctional thymic microenvironment, where T cell migration, proliferation and maturation are compromised, contributing for the thymic atrophy observed in malnourished animals. All these alterations affect the control of the local and systemic infection, resulting in an impaired response to L. infantum infection.
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Project description:During development, cortical (c) and medullary (m) thymic epithelial cells (TEC) arise from the third pharyngeal pouch endoderm. Current models suggest that within the thymic primordium most TEC exist in a bipotent/common thymic epithelial progenitor cell (TEPC) state able to generate both cTEC and mTEC, at least until embryonic day 12.5 (E12.5) in the mouse. This view however, is challenged by recent transcriptomics and genetic evidence. We therefore set out to investigate the fate and potency of TEC in the early thymus. Here using single cell (sc) RNAseq we identify a candidate mTEC progenitor population at E12.5, consistent with recent reports. Via lineage-tracing we demonstrate this population is mTEC fate-restricted, validating our bioinformatics prediction. Using potency analyses we also establish that most E11.5 and E12.5 progenitor TEC are cTEC-fated. Finally we show that overnight culture causes most if not all E12.5 cTEC-fated TEPC to acquire functional bipotency, and provide a likely molecular mechanism for this changed differentiation potential. Collectively, our data overturn the widely held view that a common TEPC predominates in the E12.5 thymus, showing instead that sublineage-primed progenitors are present from the earliest stages of thymus organogenesis but that these early fetal TEPC exhibit cell-fate plasticity in response to extrinsic factors. Our data provide a significant advance in understanding of fetal thymic epithelial development and thus have implications for thymus-related clinical research, in particular research focussed on generating TEC from pluripotent stem cells.
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