An aberrant immune-epithelial progenitor niche drives post-viral lung sequelae [human]
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ABSTRACT:
PROVIDER: PRJNA1110274 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28995918.fastq.gz | Fastqsanger.gz | |||
| SRR28995919.fastq.gz | Fastqsanger.gz | |||
| SRR28995920.fastq.gz | Fastqsanger.gz | |||
| SRR28995921.fastq.gz | Fastqsanger.gz | |||
| SRR28995922.fastq.gz | Fastqsanger.gz |
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Project description:An aberrant immune-epithelial progenitor niche drives post-viral lung sequelae [mouse]
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Project description:Respiratory viral infections are being increasingly recognized not just for their acute impact but also as potential triggers of long-term health conditions. The recent COVID-19 pandemic in particular has highlighted the prevalence of this phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), which has rapidly evolved into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or impaired organ recovery post infection. Yet, the precise mechanisms linking non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC. Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. CD8+ T cell derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate an aberrant immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
2024-08-25 | GSE267226 | GEO
Project description:Respiratory viral infections are being increasingly recognized not just for their acute impact but also as potential triggers of long-term health conditions. The recent COVID-19 pandemic in particular has highlighted the prevalence of this phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), which has rapidly evolved into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or impaired organ recovery post infection. Yet, the precise mechanisms linking non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC. Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. CD8+ T cell derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate an aberrant immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
2024-08-25 | GSE267228 | GEO
Project description:Specialized niche environments specify and maintain stem and progenitor cells, but little is known about the identities and functional interactions of niche components in vivo. Here, we describe a modular system for the generation of artificial hematopoietic niches in the mouse embryo. A circumscribed tissue that lacks niche function but is physiologically accessible for hematopoietic progenitor cells is functionalized by individual and combinatorial expression of four factors, the chemokines Ccl25 and Cxcl12, the cytokine Scf and the Notch ligand DLL4. The distinct phenotypes and variable numbers of hematopoietic cells in the resulting niches reveal synergistic, context-dependent and hierarchical interactions among niche effector molecules. The surprisingly simple rules determining niche outcomes enable the in vivo engineering of artificial niches conducive to the presence of distinct myeloid or T or B lymphoid lineage precursors. The dataset comprises 24 samples divided into eight sample groups each representing a different lymphoid progenitor cell type isolated from wild-type (+/-) or transgenic (-/-) thymic niches. -/-, Foxn1-deficient genotype; +/-, Foxn1 heterozygous phenotype; DP, CD4/CD8 double-poisztive thymocytes; DN3, CD4/CD8-negative stage 3 thymocytes; SP4, CD4 single-positive thymocytes; SP8, CD8 single-positive thymocytes; B IgM-, IgM surface negative B cells; B IgM+, IgM surface positive B cells; B IgM- -/-, IgM surface negative B cells from Foxn1-deficient genotype.
2012-08-24 | E-GEOD-33268 | biostudies-arrayexpress
Project description:Specialized niche environments specify and maintain stem and progenitor cells, but little is known about the identities and functional interactions of niche components in vivo. Here, we describe a modular system for the generation of artificial hematopoietic niches in the mouse embryo. A circumscribed tissue that lacks niche function but is physiologically accessible for hematopoietic progenitor cells is functionalized by individual and combinatorial expression of four factors, the chemokines Ccl25 and Cxcl12, the cytokine Scf and the Notch ligand DLL4. The distinct phenotypes and variable numbers of hematopoietic cells in the resulting niches reveal synergistic, context-dependent and hierarchical interactions among niche effector molecules. The surprisingly simple rules determining niche outcomes enable the in vivo engineering of artificial niches conducive to the presence of distinct myeloid or T or B lymphoid lineage precursors.
2012-08-24 | GSE33268 | GEO
Project description:Most vertebrate organs are composed of epithelium surrounded by support and stromal tissues formed from mesenchyme cells, which are not generally thought to form organized progenitor pools. Here we use clonal cell labeling with multicolor reporters to characterize individual mesenchymal progenitors in the developing mouse lung. We observe a diversity of mesenchymal progenitor populations with different locations, movements, and lineage boundaries. Airway smooth muscle (ASM) progenitors map exclusively to mesenchyme ahead of budding airways. Progenitors recruited from these tip pools differentiate into ASM around airway stalks; flanking stalk mesenchyme can be induced to form an ASM niche by a lateral bud or by an airway tip plus focal Wnt signal. Thus, mesenchymal progenitors can be organized into localized and carefully controlled domains that rival epithelial progenitor niches in regulatory sophistication. Mesenchyme was microdissected from e11.5 and e12.5 lung branch tips and stalks and profiled directly. Another set of stalk dissections were cultured in either control media or media containing Wnt1. All experiments done in duplicate.
2014-10-04 | E-GEOD-62039 | biostudies-arrayexpress
Project description:ATRX guards against aberrant differentiation in mesenchymal progenitor cells
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Project description:Immune signatures underlying post-acute COVID-19 lung sequelae
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Project description:Niche stiffness underlies the aging of CNS progenitor cells.
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Project description:Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
2022-02-01 | E-MTAB-10129 | biostudies-arrayexpress