Transcriptome in alveolar epithelial type II-like cells differentiated from human lung progenitor cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE33825 | GEO | 2012/10/11
SECONDARY ACCESSION(S): PRJNA148195
REPOSITORIES: GEO
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Project description:Resident stem/progenitor cells in lungs are important for tissue homeostasis and repair. We isolated human lung progenitor cells and named alveolar epithelial progenitor cells (AEPCs)(Fujino N, et al. 2011. Lab Invest. 91:363). AEPCs have phenotypes of both alveolar epithelial type II (ATII) cells and mesenchymal stem cells. AEPCs had the potential to generate ATII-like cells in vitro. ATII-like cells derived from AEPCs expressed protein and mRNA of pulmonary surfactant, and displayed lamellar bodies containing the surfactants. However, it has not been evaluated whether global gene expression of the ATII-like cells from AEPCs was similar to that of mature ATII cells isolated from human lung tissues. This study demonstrated gene expression profiles of ATII-like cells from AEPCs. In addition, transcriptomes in AEPCs and mature ATII cells were deposited in the GEO website (GSE21095 and GSE29133, respectively). We isolated AEPCs from tissue samples obtained from patients who underwent lung resection at Department of Thoracic Surgery, Tohoku University Hospital. We induced differentiation of AEPCs to ATII-like cells on extracellular matrix with medium containing KGF, cAMP and IBMX, as previously described (Fujino N, et al. 2011. Lab Invest. 91:363). We profiled the gene expression in three different batches of the ATII-like cells. We extracted total RNA from the differentiated cells. This study was approved by the Ethics Committee at Tohoku University School of Medicine. All subjects gave informed consent.
2012-10-11 | E-GEOD-33825 | biostudies-arrayexpress
Project description:Resident stem/progenitor cells in the lung are important for tissue homeostasis and repair. However, a progenitor population for alveolar type II (ATII) cells in adult human lungs have not been identified. Here we isolated alveolar epithelial progenitor cells (AEPCs) from adult human lungs. AEPCs showed mesenchymal stem cell (MSC)-like characteristics combined with ATII cell-phenotypes. AEPCs had the capability for self-renewal and the potential to generate ATII cells in vitro. Furthermore, cells expressing similar markers were present within alveolar walls in normal lungs and these cells were significantly increased in ATII cell hyperplasias. These results suggest that adult human lungs contain a progenitor population for ATII cells.
2010-11-16 | GSE21095 | GEO
Project description:Alveolar epithelial type II (ATII)-like cells can be generated from murine embryonic stem cells (ESCs), although to date, no robust protocols applying specific differentiation factors are established. We hypothesized that the keratinocyte growth factor (KGF), an important mediator of lung organogenesis and primary ATII cell maturation and proliferation, together with dexamethasone, 8-bromoadenosine-cAMP, and isobutylmethylxanthine (DCI), which induce maturation of primary fetal ATII cells, also support the alveolar differentiation of murine ESCs. Here we demonstrate that the above stimuli synergistically potentiate the alveolar differentiation of ESCs as indicated by increased expression of the surfactant proteins (SP-) C and SP-B. This effect is most profound if KGF is supplied not only in the late stage, but at least also during the intermediate stage of differentiation. Our results indicate that KGF most likely does not enhance the generation of (mes)endodermal or NK2 homeobox 1 (Nkx2.1) expressing progenitor cells but rather, supported by DCI, accelerates further differentiation/maturation of respiratory progeny in the intermediate phase and maturation/proliferation of emerging ATII cells in the late stage of differentiation. Ultrastructural analyses confirmed the presence of ATII-like cells with intracellular composite and lamellar bodies. Finally, induced pluripotent stem cells (iPSCs) were generated from transgenic mice with ATII cell-specific lacZ reporter expression. Again, KGF and DCI synergistically increased SP-C and SP-B expression in iPSC cultures, and lacZ expressing ATII-like cells developed. In conclusion, ATII cell-specific reporter expression enabled the first reliable proof for the generation of murine iPSC-derived ATII cells. In addition, we have shown KGF and DCI to synergistically support the generation of ATII-like cells from ESCs and iPSCs. Combined application of these factors will facilitate more efficient generation of stem cell-derived ATII cells for future basic research and potential therapeutic application. 10 samples in total. mESCs at d8 of differentiation (Control) mESCs at d8 of differentiation with KGF treatment mESCs at d17 of differentiation (Control) mESCs at d17 of differentiation with KGF treatment mESCs at d17 of differentiation with DCI treatment mESCs at d17 of differentiation with KGF and DCI treatment mESCs at d24 of differentiation (Control) mESCs at d24 of differentiation with KGF treatment mESCs at d24 of differentiation with DCI treatment mESCs at d24 of differentiation with KGF and DCI treatment
2013-01-01 | E-GEOD-33308 | biostudies-arrayexpress
Project description:Alveolar epithelial type II (ATII)-like cells can be generated from murine embryonic stem cells (ESCs), although to date, no robust protocols applying specific differentiation factors are established. We hypothesized that the keratinocyte growth factor (KGF), an important mediator of lung organogenesis and primary ATII cell maturation and proliferation, together with dexamethasone, 8-bromoadenosine-cAMP, and isobutylmethylxanthine (DCI), which induce maturation of primary fetal ATII cells, also support the alveolar differentiation of murine ESCs. Here we demonstrate that the above stimuli synergistically potentiate the alveolar differentiation of ESCs as indicated by increased expression of the surfactant proteins (SP-) C and SP-B. This effect is most profound if KGF is supplied not only in the late stage, but at least also during the intermediate stage of differentiation. Our results indicate that KGF most likely does not enhance the generation of (mes)endodermal or NK2 homeobox 1 (Nkx2.1) expressing progenitor cells but rather, supported by DCI, accelerates further differentiation/maturation of respiratory progeny in the intermediate phase and maturation/proliferation of emerging ATII cells in the late stage of differentiation. Ultrastructural analyses confirmed the presence of ATII-like cells with intracellular composite and lamellar bodies. Finally, induced pluripotent stem cells (iPSCs) were generated from transgenic mice with ATII cell-specific lacZ reporter expression. Again, KGF and DCI synergistically increased SP-C and SP-B expression in iPSC cultures, and lacZ expressing ATII-like cells developed. In conclusion, ATII cell-specific reporter expression enabled the first reliable proof for the generation of murine iPSC-derived ATII cells. In addition, we have shown KGF and DCI to synergistically support the generation of ATII-like cells from ESCs and iPSCs. Combined application of these factors will facilitate more efficient generation of stem cell-derived ATII cells for future basic research and potential therapeutic application.
2013-01-01 | GSE33308 | 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:Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2-4 years. Injury to and/or dysfunction of alveolar epithelium are strongly implicated in IPF disease initiation, but what factors determine why fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that ZEB1-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments TGF-β-induced profibrogenic responses in underlying lung fibroblasts by paracrine signalling. Here we investigated bi-directional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA sequencing (RNA-seq) of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced EMT identified many differentially expressed genes including those involved in cell migration and extracellular matrix (ECM) regulation. We confirmed that paracrine signalling between AS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a ZEB1-tissue plasminogen activator (tPA) axis. In a reciprocal fashion, paracrine signalling from TGF-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially via the secreted protein, SPARC. Together these data identify that aberrant bi-directional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining pro-fibrotic signals.
2021-08-19 | PXD025821 | Pride
Project description:Alveolar epithelial type II (ATII) cells play a critical role in homeostasis and repair process of the lungs. In lung diseases such as chronic obstructive pulmonary disease (COPD), ATII cells are damaged and fall into apoptosis or senescence. Until to date, global gene expression of ATII cells in COPD lungs has not been analyzed. We isolated ATII cells from three non-COPD and three COPD patients using a FACS method. Then, we performed microarray analysis to compare gene expression profiles of ATII cells between non-COPD and COPD patients.
2012-10-11 | GSE29133 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and lethal lung disease. The initiation of IPF involves microinjuries to and/or dysfunction of the alveolar epithelium, but factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signalling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells induces autophagy inhibition and EMT as a consequence. In IPF lungs, this is caused by a downregulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and lung fibroblast MRC5 coupled with RNA sequencing (RNA-seq) confirmed that paracrine signalling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.
2023-08-09 | GSE205965 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and lethal lung disease. The initiation of IPF involves microinjuries to and/or dysfunction of the alveolar epithelium, but factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signalling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells induces autophagy inhibition and EMT as a consequence. In IPF lungs, this is caused by a downregulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and lung fibroblast MRC5 coupled with RNA sequencing (RNA-seq) confirmed that paracrine signalling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.
2023-08-09 | GSE205969 | GEO
Project description:To define the role of Yap/Taz in alveolar epithelial regeneration, we deleted Yap/Taz in mouse lung Spc-expressing ATII cells by using Spc-CreERT2, Yap fl/fl, Taz fl/fl, R26R-mTmG mice. This data set contains the microarrays examining gene expression in the lineage-labeled Spc-expressing ATII cells before and after Streptococcus pneumoniae infection.
2018-12-01 | GSE86027 | GEO