Gene expression profile at single cell level of total alveolar type II (AT2) cells and CD44hi AT2 cells
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ABSTRACT:
PROVIDER: PRJNA835085 | ENA |
REPOSITORIES: ENA
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Project description:AT2 cells are the resident progenitor cells in alveoli, capable of self-proliferation and differentiation into alveolar type I cells during homeostatic maintenance and tissue regeneration. The AT2 cell population is heterogenous. We identified a small subpopulation of AT2 cells that express high levels of CD44 (CD44hi) and display progenitor functions during alveoli homeostasis. To further analyze the heterogeneity of the AT2 cell population and characterize CD44hi AT2 cells, we performed single cell RNA-seq on the total AT2 cell population and CD44hi AT2 cells.
2024-05-24 | GSE202226 | GEO
Project description:The epithelium of alveoli is composed of alveoli type I cells (AT1) that cover ~95% of the surface area and alveoli type II cells (AT2) that secret surfactant as well as function as adult stem cells. To characterize a subgroup of AT2 that express higher levels of hyaluronan receptor CD44 (the CD44high, or CD44hi AT2) and behave as alveoli epithelial stem cells during steady-state homeostasis, we used RNA-sequencing to compare the expression profiles of these cells with the bulk CD44low (or CD44lo ) AT2. CD44hi AT2 showed gene signatures that indicate partial de-differentiation and a higher potential to proliferate compared with CD44lo AT2. At steady-state conditions, CD44hi AT2 also showed higher expression of genes activated by NFκB mediated inflammatory responses and transcriptome signatures that resemble early-stage Kras-induced adenocarcinoma. Furthermore, these cells were more responsive to KrasG12D induction both in 3D tumor organoid culture and in mouse lung cancer cell transplantation models. In summary, CD44hi AT2 plays an essential role in the homeostatic maintenance of the alveolar epithelium and tumor initiation.
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Project description:The epithelium of alveoli is composed of alveoli type I cells (AT1) that cover ~95% of the surface area and alveoli type II cells (AT2) that secret surfactant as well as function as adult stem cells. CD44hi subpopulation of AT2 cells exhibits higher potential to proliferate and differentiate under steady state conditions. To understand the CD44hi subpopulation of AT2 cells after lung injury, we assessed those cells in a Pseudomonas aeruginosa (PA) induced mouse model of lung injury. CD44hi and CD44low AT2 cells were FACS sorted from untreated and 3d PA treated mice. In addition, since Sca1+ AT2 cells were shown to emerge during the repair phase of the PA induced injury in our earlier studies, we also isolated Sca1+ AT2 cells at 3d post PA injury to compare with the CD44hi subpopulation. RNA-seq was used to compare the expression profile of the different subgroups of AT2 cells.
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Project description:The pulmonary alveolar epithelium mainly composed of two types of epithelial cells: alveolar type I (AT1) and type II (AT2) cells. AT2 cells are the alveolar stem cells, and can differentiate into AT1 cells post-pneumonectomy (PNX). Here, we found that, compared with control mice (Sftpc-CreER; Cdc42flox/+; Rosa26-mTmG) at post-PNX day 21, Cdc42 AT2 null mice (Sftpc-CreER; Cdc42flox/-; Rosa26-mTmG) at post-PNX day 21 undergone fibrotic change. By using 10X genomics “Chromium Single Cell” technology, we performed single-cell RNA-seq analyses of AT2 cells of sham treated control mice (C0), AT2 cells of control mice at post PNX day 21 (C21) , AT2 cells of sham treated Cdc42 AT2 null mice (N0), and AT2 cells of Cdc42 AT2 null mice at post PNX day 21 (N21). The study identified a specific gene signature in AT2 cells of Cdc42 AT2 null mice at post PNX day 21 which is related to the fibrosis phenotype of Cdc42 AT2 null mice.
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Project description:Profiling AT1 and AT2 cells throughout alveolar development
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Project description:Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential tomaintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin- RING ubiquitin ligase CRL4COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.
2018-03-08 | GSE111569 | GEO
Project description:Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, Damage-Associated Transient Progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this step-wise mapping to cell fate transitions shows how an inflammatory niche impairs alveolar regeneration by controlling stem cell fate and behavior.
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Project description:Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, Damage-Associated Transient Progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this step-wise mapping to cell fate transitions shows how an inflammatory niche impairs alveolar regeneration by controlling stem cell fate and behavior.
2020-08-03 | GSE144598 | GEO
Project description:Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, Damage-Associated Transient Progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this step-wise mapping to cell fate transitions shows how an inflammatory niche impairs alveolar regeneration by controlling stem cell fate and behavior.
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