Project description:Human early embryos develop under physiological hypoxia, but how hypoxia regulates human lung organogenesis remains little known. We have investigated oxygen availability effects on the human lung epithelium using organoids. We find first-trimester lung epithelial progenitors remain undifferentiated under normoxia, but spontaneously differentiate towards multiple airway cell types and inhibit alveolar differentiation under hypoxia. Using chemical and genetic tools, we demonstrate that hypoxia-induced airway differentiation is dependent on HIF (Hypoxia-Inducible Factor) pathways, with HIF1α and HIF2α differentially regulating fate decisions. Transcription factors KLF4 and KLF5 are direct targets of the HIF pathway and promote progenitor differentiation to basal and secretory cells. Chronic hypoxia also reprogrammed human alveolar type 2 cells to airway cells via the HIF pathway. Our results reveal roles for hypoxia and HIF signalling during human lung development and have implications for aberrant cell fate decisions in chronic lung diseases.
Project description:Human embryos develop under physiological hypoxia, but how hypoxia directly affects human organogenesis remains unknown. We have investigated the effects of hypoxia on human lung epithelia using organoids. First trimester lung epithelial progenitors remain undifferentiated under normoxia, but initiate spontaneous differentiation towards multiple airway cell types, and inhibit alveolar differentiation under hypoxia. Genetic and chemical manipulation experiments showed that these effects were dependent on HIF (Hypoxia-Inducible Factor) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. We identified the cell fate-determining transcription factors KLF4/KLF5 and ASCL1 as direct targets of the HIF pathway, promoting progenitor differentiation to basal and neuroendocrine cells respectively. Chronic hypoxia also induces transdifferentiation of human alveolar type 2 cells into airway cells via the HIF pathway, suggesting that the developmental response to hypoxia is conserved into adulthood and potentially contributes to chronic lung disease.
Project description:Human embryos develop under physiological hypoxia, but how hypoxia directly affects human organogenesis remains unknown. We have investigated the effects of hypoxia on human lung epithelia using organoids. First trimester lung epithelial progenitors remain undifferentiated under normoxia, but initiate spontaneous differentiation towards multiple airway cell types, and inhibit alveolar differentiation under hypoxia. Genetic and chemical manipulation experiments showed that these effects were dependent on HIF (Hypoxia-Inducible Factor) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. We identified the cell fate-determining transcription factors KLF4/KLF5 and ASCL1 as direct targets of the HIF pathway, promoting progenitor differentiation to basal and neuroendocrine cells respectively. Chronic hypoxia also induces transdifferentiation of human alveolar type 2 cells into airway cells via the HIF pathway, suggesting that the developmental response to hypoxia is conserved into adulthood and potentially contributes to chronic lung disease.
Project description:Human embryos develop under physiological hypoxia, but how hypoxia directly affects human organogenesis remains unknown. We have investigated the effects of hypoxia on human lung epithelia using organoids. First trimester lung epithelial progenitors remain undifferentiated under normoxia, but initiate spontaneous differentiation towards multiple airway cell types, and inhibit alveolar differentiation under hypoxia. Genetic and chemical manipulation experiments showed that these effects were dependent on HIF (Hypoxia-Inducible Factor) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. We identified the cell fate-determining transcription factors KLF4/KLF5 and ASCL1 as direct targets of the HIF pathway, promoting progenitor differentiation to basal and neuroendocrine cells respectively. Chronic hypoxia also induces transdifferentiation of human alveolar type 2 cells into airway cells via the HIF pathway, suggesting that the developmental response to hypoxia is conserved into adulthood and potentially contributes to chronic lung disease.
Project description:In this study, we assessed lower airway microbiome from a cohort of patients to determine whether specific microbiome taxa correlate with with specific metabolic activities. In a subset of 12 patients, transcriptomic expression were analyzed to compare host mucosa immune response We collected peripheral airway brushings from the 12 subjects whose lung microbiome were analyzed; Total RNA were obtained from the peripheral airway epithelium.