Profiling AT1 and AT2 cells throughout alveolar development
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ABSTRACT:
PROVIDER: PRJNA624469 | ENA |
REPOSITORIES: ENA
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Project description:This experiment profiled the transcriptomes of developing AT1 and AT2 cells from the beginning of embryonic alveolar development through the end of alveologenesis at 6 weeks of age.
2021-05-20 | GSE148487 | GEO
Project description:Hypercapnia has deleterious effects on cell function, including inhibition of alveolar epithelial cells (AEC) and fibroblast proliferation without causing cell death. Classical studies and lineage-trace models demonstrated that surfactant-producing AT2 cells can serve as stem cells for the structurally and functionally distinct alveolar type 1 cells (AT1) This AT2 reprogramming depends on Wnt/βcat signaling, a pathway that plays critical roles in tissue development and homeostasis throughout the organism lifespan. We found that high CO2 inhibits AT2 cell proliferation and self renewal, and promote their differentiation to ATEC and AT1 cells
2021-12-31 | GSE139426 | GEO
Project description:Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease increasing in incidence which disrupts lung health throughout the lifespan. The TGFβ superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that the primary TGFβ receptor, Tgfbr2, is critical for AT1 cell fate maintenance and function. Loss of Tgfbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analysis reveal that expression of extracellular matrix components by AT1 cells is attenuated with loss of Tgfbr2. Cell spreading assays shows that TGFβ signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGFβ signaling to maintain AT1 fate and define this cell lineage as a major orchestrator of the alveolar matrisome, which, if altered, may predispose to BPD.
2024-03-04 | GSE230268 | GEO
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.
2020-01-03 | GSE138585 | GEO
Project description:Alveolar epithelial cell fate decisions drive lung development and regeneration. Using transcriptomic and epigenetic profiling coupled with genetic mouse and organoid models, we identified Klf5 as a critical regulator of alveolar epithelial cell fate across the lifespan. During prenatal lung development and alveologenesis, Klf5 enforces alveolar epithelial type 1 (AT1) cell lineage fidelity. While it is dispensable for both adult AT1 and alveolar epithelial type 2 (AT2) cell homeostasis, Klf5 regulates AT2 cell plasticity after injury. Klf5 represses AT2 cell proliferation and enhances AT2-AT1 cell differentiation in a spatially restricted manner in both infectious and non-infectious models of acute respiratory distress syndrome. Moreover, ex vivo organoid assays reveal that Klf5 modulates AT2 cell fate decisions through reducing AT2 cell sensitivity to inflammatory signaling. These data highlight a major transcriptional regulator of AT1 cell lineage commitment and of the AT2 cell response to inflammatory crosstalk during lung regeneration.
2022-06-08 | GSE190676 | 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.
2020-08-03 | GSE145031 | 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.
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.
2020-08-03 | GSE144468 | GEO
Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.
2014-03-07 | E-GEOD-49346 | biostudies-arrayexpress
Project description:Analysis of gene expression during differentiation of alveolar epithelial type 2 (AT2) cells into AT1 cells. Timepoints taken at Day 0 (AT2 cell), Days 2, 4, and 6 in culture (differentiating) and Day 8 in culture (AT1-like cells). 1ug of RNA was subjected to cRNA conversion using Illumina TotalPrep RNA kit and hybridized to the HT12v4 array Analysis of gene expression during differentiation of alveolar epithelial type 2 (AT2) cells into AT1 cells
2013-04-15 | E-GEOD-38570 | biostudies-arrayexpress