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P63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (transplanted and damaged)

ABSTRACT: The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE60830 | GEO | 2014/11/20

SECONDARY ACCESSION(S): PRJNA259663

REPOSITORIES: GEO

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p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (transplanted and damaged)

Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. Transplanted DASC cells incorporated into damaged host lung were laser capture microdissected and analyzed. Duplicate mice were included. We used the Affymetrix Mouse Exon 1.0 ST platform

2014-11-20 | E-GEOD-60830 | biostudies-arrayexpress

p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (Dtox treatment)

2014-11-20 | GSE60829 | GEO

p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (before and after in vitro differentiation)

2014-11-20 | GSE60828 | GEO

p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (Dtox treatment)

Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. DASC stem cells were ablated by Dtox treatment in Krt6:DTR mouse model. Control and stem cell ablated lungs were analyzed. We used the Affymetrix Mouse Exon 1.0 ST platform

2014-11-20 | E-GEOD-60829 | biostudies-arrayexpress

p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (tracheal epithelium and alveoli)

Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases.

2014-11-20 | GSE61091 | GEO

p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (before and after in vitro differentiation)

Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. Stem cells before and after in vitro differentiation were subjected to whole genome microarray analysis. Duplicates were included for each sample. We used the Affymetrix Mouse Exon 1.0 ST platform

2014-11-20 | E-GEOD-60828 | biostudies-arrayexpress

p63+/Krt5+ Distal Airway Stem Cells are Essential for Lung Regeneration (tracheal epithelium and alveoli)

Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. Tracheal epithelium and alveoli of healthy mice were laser capture microdissected for microarray analysis. Damaged lung interstitium (CD45+ region) of influenza infected (75pfu H1N1, 15dpi) mice were also dissected. Duplicates were included for each sample. We used the Affymetrix Mouse Exon 1.0 ST platform

2014-11-20 | E-GEOD-61091 | biostudies-arrayexpress

Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection (LCM_Four populations of cells)

Project description:The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel findings that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease. H1N1 infected mice were sacrificed at 25 dpi and the lungs were snap frozen and embedded in OCT. Sections were cut and stained for several markers and consecutive sections were used for Laser Capture Microdissection.The PALMM-BM-. Robot Microbeam laser microdissection system (P.A.L.M. GmbH, Bernried, Germany) in combination with a Zeiss microscope was used to dissect out desired cells.Four population of cells were collected namely alveoli, Krt5+,Spc+ and K5&SPC-. Isolated cells were collected in adhesive caps (Carl Zeiss, Inc.) and RNA was extracted using the Pico Pure RNA extraction kit (Arcturus).

2011-11-01 | E-GEOD-32602 | biostudies-arrayexpress

Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection (colony)

Project description:The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel findings that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease. 3 colonies fron control and H1N1 influenza treated lungs (12 dpi) ,each were picked for whole genome microarray analysis

2011-11-01 | E-GEOD-32600 | biostudies-arrayexpress

Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis

Project description:Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we show an association between KRT5+ cells in human fibrotic lung and regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry-based proteomics revealed compositional differences in the matrisome secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrisome restricts KRT5+ cell migration in vitro. Together, our findings demonstrate that changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

2023-09-28 | PXD037236 | Pride

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