Transcriptional profiling of CD44hi AT2 cells under homeostasis and after lung injury [I]
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ABSTRACT:
PROVIDER: PRJNA757438 | ENA |
REPOSITORIES: ENA
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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.
2024-05-23 | GSE267236 | 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.
2024-05-23 | GSE182699 | GEO
Project description:Transcriptional profiling of CD44hi AT2 cells under homeostasis and after lung injury [II]
| PRJNA1110583 | ENA
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: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:Autophagy is a cellular catabolic process that supports metabolism in response to stress. To identify gene expression that are modulated by autophagy in AT2 cells during BLM-induced lung injury, RNA-seq profiling were carried out with AT2 cells from Atg5f/f mice treated with PBS (AT2-PBS), Nkx2.1Cre; Atg5f/f mice treated with PBS (Atg5−/− AT2-PBS), Atg5f/f mice treated with BLM (AT2-BLM), and Nkx2.1Cre; Atg5f/f mice treated with BLM (Atg5−/− AT2-BLM) at day 14. We found the glycolytic and pentose phosphate pathways were promoted, but that the synthesis of fatty acids was repressed in mouse AT2 cells during BLM injury. Autophagy may serve as a switch between these two metabolic pathways during lung injury. These data highlight an essential role for autophagy in reprogramming the metabolism of alveolar progenitor cells to meet energy needs for alveolar epithelial regeneration.
2020-01-08 | GSE143212 | GEO
Project description:Alveolar type 2 (AT2) cells are stem cells of the alveolar epithelia. Previous genetic lineage tracing studies reported multiple cellular origins for AT2 cells after injury. However, conventional lineage tracing based on Cre-loxP has the limitation of non-specific labeling. Thus, the exact contribution of various epithelial cells to the pools of AT2 cells under different conditions remains unclear. Here, we used dual recombinases-mediated intersectional genetic lineage tracing to investigate the cellular origins of AT2 cells during lung homeostasis, injury and repair. In contrast to previous studies, we found AT1 cells were terminally differentiated cells and did not contribute to AT2 cells after lung injury and repair. Distinctive, but simultaneous, labeling of club cells, bronchioalveolar stem cells (BASCs), and AT2 cells revealed the exact contribution of each to AT2 cells after lung injury. Moreover, we found that club cells have the potential to rebuild virtually all alveoli in some severely injured lung regions. Mechanistically, Notch signaling promotes a BASCs-to-AT2 cell transition, but it inhibits club cell-to-AT2 cell conversion during lung repair. This intersectional genetic lineage tracing strategy with enhanced precision allowed us to elucidate the physiological role of AT1, club, BASCs, and AT2 cells to alveolar regeneration after injury.
2024-01-06 | GSE252588 | GEO
Project description:RNA-seq was performed to understand transcriptome changes with Mfsd2a deficiency in lung AT2 cells. Gene expression analysis was performed using DESeq2.
2022-02-07 | GSE186170 | GEO
Project description:Characterization of Mfsd2a-deficient lung AT2 cells.
| PRJNA772766 | ENA
Project description:Alveolar type 1 and type 2 cells comprise the epithelial component of the lung alveolus where gas exchange occurs. AT2 cells harbor progenitor activity and can self-renew and differentiate into AT1 cells during homeostasis and after injury. To identify epigenetic pathways that control the AT2-AT1 regenerative response in the lung, we performed an organoid screen using a library of pharmacological epigenetic inhibitors. This screen identified Dot1L as a potential regulator of AT2 growth and differentiation. To explore the role of Dot1L in vivo, we genetically inactivated Dot1L during lung development, showing that this leads to precocious activation of both AT1 and AT2 gene expression. Loss of Dot1L in adult AT2 cells leads to accelerated AT1 differentiation after acute lung injury. Single cell transcriptome analysis of lineage traced AT2 cells reveals the presence of a new AT2 cell state upon loss of Dot1L, and reveals that Dot1L regulates a complex gene expression network that includes critical transcription factors such as Id1 and Id2 and oxidative phosphorylation genes. Taken together, these data demonstrate that Dot1L regulates an epigenetic pathway in the lung essential for alveolar epithelial development and regeneration after acute injury.
2023-10-11 | GSE210800 | GEO