A grainyhead transcription factor Tfcp2l1 controls the timing for lung alveolar regeneration (scRNA-Seq)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE204786 | GEO | 2023/09/12
REPOSITORIES: GEO
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Project description:Alveolar epithelial type 2 (AT2) cells are facultative progenitor cells that drive adult alveolar regeneration after acute lung injury. Using transcriptomic analyses from in vivo mouse injury models, we define the role of Tfcp2l1 in regulating AT2 cell behavior during lung regeneration.
2023-09-12 | GSE204784 | GEO
Project description:Lung injury activates potential stem cells or progenitors for alveolar repair and regeneration. However, the activation program and source of injury-induced facultative progenitors remain incompletely known. Here, we find that lung injury induces emergence of p63-expressing progenitors, which rapidly proliferate and differentiate into alveolar type-1 (AT1) and type-2 (AT2) cells. scRNA-seq analysis uncovers that a subset of p63+ progenitors exhibit two distinct parallele transient stages before differentiation into mature AT1 and AT2 cells, respectively. Dual recombinases-mediated sequential genetic tracing reveals that facultative p63+ progenitors originate from the distal airway secretory cells and subsequently regenerate alveoli. Functioanlly, secretory cell-specific knockout of p63 significantly impairs their contribution to alveolar epithelium during lung regeneration. Our study identified secretory cell-derived facultative p63+ progenitors that contribute to alveolar regeneration, indicating a potential therapeutic target for lung treatment after injuires.
2023-02-20 | GSE225187 | 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:Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing datasets of human interstitial lung disease, we found that interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ and basaloid cells. Stimulation of AT2 cells with IL11 or TGFβ1 caused EMT, induced KRT8+ and stalled AT1 differentiation, with TGFβ1 effects being IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived KRT8+ cells and deletion of Il11ra1 in lineage labeled AT2 cells reduced KRT8+ expression, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11. These data show that IL11 maintains AT2 cells in a dysfunctional transitional state, impairs AT1 differentiation and blocks alveolar regeneration across species.
2024-08-12 | GSE218386 | 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:A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings established that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.
2023-11-15 | GSE243135 | 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:Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in injury-repair. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development through differentiation of lung progenitor organoids to AT2 cells and benchmarking against primary AT2 organoids.
2023-06-15 | E-MTAB-12960 | biostudies-arrayexpress
Project description:Aging-related impairment in alveolar regeneration has been identified in a variety of acute and chronic lung diseases. As the aging population increases, understanding the mechanisms involved in age-dependent deterioration in alveolar stem cell function can support the development of new therapies for lung diseases. In this study, we investigated the cellular and molecular mechanisms underlying AT2 cell differentiation and how aging affected post-injury alveolar regeneration. We discovered that the process of AT2 cells differentiating into AT1 cells is an energetically costly process. During the differentiation of AT2 cells, activated AMPK-PFKFB2 signaling up-regulates glycolysis, which is essential to enhance cellular ATP production and to support the intracellular energy expenditure that is required for cell shape change and cytoskeletal remodeling during AT2 cells differentiating into AT1 cells. AT2 cells in aging lungs show reduced AMPK-PFKFB2 signaling and decreased ATP production, resulting in impaired AT2 cell differentiation. Activating AMPK-PFKFB2 signaling in aged AT2 cells can rescue defects in alveolar regeneration. Thus, beyond demonstrating that the activation of AMPK-PFKFB2 signaling facilitates the great energy demands of AT2 cells during alveolar regeneration, our study suggests that modulating these pathways could promote the alveolar repair in aged lungs.
2022-05-01 | GSE186246 | GEO
Project description:Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT2 and AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing (scRNA-seq) datasets of human interstitial lung disease, we found that Interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ epithelial cells and basaloid cells. Stimulation of AT2 cells and distal airway epithelial cells with IL11 or TGFβ1 caused epithelial-to-mesenchymal transition (EMT), induced extracellular matrix (ECM) production, increased KRT8 expression and stalled AT2-to-AT1 differentiation, with TGFβ1 effects being partially IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived Krt8+ transitional cells and deletion of Il11ra1 in AT2 lineage cells prevented the accumulation of Krt8+ transitional cells, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11 antibodies. scRNA-seq analysis of lung epithelial cells from mice with deletion of Il11ra1 in AT2 lineage cells further identified the importance of IL11 signaling for the potentiation and polarization of a disease-causing, ECM producing KRT8+ transitional cells that contributes to pathological lung remodeling. Overall, our data show that IL11 maintains damaged AT2 cells in a transitional state, impairs reparative AT1 differentiation and impairs endogenous alveolar regeneration to cause fibrotic lung disease.
2024-08-12 | GSE261793 | GEO