A correctable immune niche for epithelial stem-cell reprogramming and post-viral lung diseases
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1130060 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29657300.fastq.gz | Fastqsanger.gz | |||
| SRR29657301.fastq.gz | Fastqsanger.gz | |||
| SRR29657302.fastq.gz | Fastqsanger.gz | |||
| SRR29657303.fastq.gz | Fastqsanger.gz | |||
| SRR29657288.fastq.gz | Fastqsanger.gz |
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Project description:A correctable immune niche for basal-epithelial stem-cell reprogramming and post-viral lung diseases
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Project description:Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cell (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identify a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functions as an early sentinel niche for basal-ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depends on moDC delivery of ligand Gpnmb to basal-ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provides long-lasting correction of reprogramming and broad disease phenotypes. These same control points work directly in mouse and human basal-ESC organoids, and corresponding biomarkers track with comparable lung diseases in humans. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury.
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Project description:Epithelial barriers are programmed for defense and repair but are also frequently the site of long-term remodeling disease. In general, this paradigm features activation of epithelial stem cells that coordinate organ development but persist into adult life to regenerate damaged tissues. Here we identify a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functions as an early sentinel niche for basal-epithelial stem cells (basal-ESC) growth and feed-forward inflammation in mouse models of epithelial injury due to respiratory viral infections. This niche function depends on Gpnmb-CD44 signaling so that transient but properly timed antibody blockade of ligand or receptor provides long-lasting disease correction in these injuries. These same control points are found for mouse and human basal-ESC-derived organoids, and the corresponding biomarkers track with comparable lung diseases in humans. Together, the findings identify a mechanism to explain and modify basal-ESC reprogramming in what is otherwise a stereotyped, primordial response to epithelial injury.
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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.
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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.
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Project description:An aberrant immune-epithelial progenitor niche drives post-viral lung sequelae [mouse]
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Project description:An aberrant immune-epithelial progenitor niche drives post-viral lung sequelae [human]
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Project description:Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provided long-lasting correction of reprogramming and broad disease phenotypes. These same control points worked directly in mouse and human basal ESC organoids. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury.
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Project description:Functional regeneration of the lung’s gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using a multi-modal approach, we have mapped the temporal sequencing of mouse lung regeneration after acute viral injury, demonstrating that this response is asynchronously phased across different cellular compartments. This longitudinal atlas of regeneration has produced a catalogue of new cell states that reflect transient and persistent transcriptional alterations in daughter cells as they transit across axes of differentiation. These new cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares transcriptional hallmarks with both developing lung endothelium and the endothelial aberrations found in degenerative human lung diseases. This comprehensive atlas of lung regeneration provides a foundational resource to understand the complexity of the cellular and molecular responses to injury, reveals the critical importance of capillary endothelium in maintaining and rebuilding the alveolar niche after injury, and correlates these responses to those found in development and human lung diseases.
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