Primary cilia as a targetable node between biliary injury, senescence and regeneration
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ABSTRACT:
PROVIDER: PRJNA911227 | ENA |
REPOSITORIES: ENA
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Project description:Biliary complications are disabling conditions that arise in up to 25% of liver transplanted patients, resulting in additional surgical procedures, re-transplantation or, in the absence of a suitable regraft, death. Here, we investigate the role of the primary cilia, a highly-specialised sensory organelle, in biliary injury leading to biliary complications. Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (N=7), compared to successful transplants (N=12). To study the biological effects of the primary cilia during transplantation, we used murine models that recapitulate liver procurement and cold storage conditions, and the K19CreERT Kif3a flox/flox mouse model to conditionally eliminate primary cilia in cholangiocytes. Microarray and RNA-seq analysis were used to study these biological effects at the transcriptional level. To explore the molecular mechanisms responsible for the observed phenotypes, we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Pharmacological and genetic approaches were used to target cellular senescence and the primary cilia, in mouse models and human donor livers. Prolonged ischemic periods pre-transplantation result in ciliary shortening and cellular senescence. Primary cilia damage results in biliary injury and a loss of regenerative potential. Initiation of senescence negatively primary cilia structure, establishing a negative feedback loop that further impairs regeneration. We conclude that primary cilia play an essential role in biliary regeneration; we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve the outcome of the liver transplanted patient.
2024-07-12 | GSE220718 | GEO
Project description:Primary cilia as a targetable node between biliary injury, senescence and regeneration [RNA-seq]
| PRJNA911234 | ENA
Project description:Biliary complications are disabling conditions that arise in up to 25% of liver transplanted patients, resulting in additional surgical procedures, re-transplantation or, in the absence of a suitable regraft, death. Here, we investigate the role of the primary cilia, a highly-specialised sensory organelle, in biliary injury leading to biliary complications. Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (N=7), compared to successful transplants (N=12). To study the biological effects of the primary cilia during transplantation, we used murine models that recapitulate liver procurement and cold storage conditions, and the K19CreERT Kif3a flox/flox mouse model to conditionally eliminate primary cilia in cholangiocytes. Microarray and RNA-seq analysis were used to study these biological effects at the transcriptional level. To explore the molecular mechanisms responsible for the observed phenotypes, we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Pharmacological and genetic approaches were used to target cellular senescence and the primary cilia, in mouse models and human donor livers. Prolonged ischemic periods pre-transplantation result in ciliary shortening and cellular senescence. Primary cilia damage results in biliary injury and a loss of regenerative potential. Initiation of senescence negatively primary cilia structure, establishing a negative feedback loop that further impairs regeneration. We conclude that primary cilia play an essential role in biliary regeneration; we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve the outcome of the liver transplanted patient.
2024-07-12 | GSE220820 | GEO
Project description:Biliary complications are disabling conditions that arise in up to 25% of liver transplanted patients, resulting in additional surgical procedures, re-transplantation or, in the absence of a suitable regraft, death. Here, we investigate the role of the primary cilia, a highly-specialised sensory organelle, in biliary injury leading to biliary complications. Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (N=7), compared to successful transplants (N=12). To study the biological effects of the primary cilia during transplantation, we used murine models that recapitulate liver procurement and cold storage conditions, and the K19CreERT Kif3a flox/flox mouse model to conditionally eliminate primary cilia in cholangiocytes. Microarray and RNA-seq analysis were used to study these biological effects at the transcriptional level. To explore the molecular mechanisms responsible for the observed phenotypes, we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Pharmacological and genetic approaches were used to target cellular senescence and the primary cilia, in mouse models and human donor livers. Prolonged ischemic periods pre-transplantation result in ciliary shortening and cellular senescence. Primary cilia damage results in biliary injury and a loss of regenerative potential. Initiation of senescence negatively primary cilia structure, establishing a negative feedback loop that further impairs regeneration. We conclude that primary cilia play an essential role in biliary regeneration; we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve the outcome of the liver transplanted patient.
2024-07-12 | GSE220720 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-07-12 | GSE220722 | GEO
Project description:Biliary diseases can cause inflammation, fibrosis, bile duct destruction and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have purified human Biliary Epithelial Cells (hBEC) from discarded human livers. hBECs were tested as a cell therapy in a mouse model of biliary disease where the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures and fibrosis. hBEC are expandable, phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease.
2022-03-03 | GSE155498 | GEO
Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05). Conclusions/significance: Models predict that a reduction in cilia length would reduce mucociliary clearance, suggesting that smoking-associated shorter airway epithelial cilia plays a significant role in the pathogenesis of smoking-induced lung disease.
2012-12-13 | E-GEOD-16696 | biostudies-arrayexpress
Project description:Identification of differential gene expression uging endoscopic biliary brushings Bile duct brishings of benign biliary strictures and malignant biliary strictures, samples snap frozen in liquid nitrogen
2012-03-01 | E-GEOD-34166 | biostudies-arrayexpress
Project description:Restitution of the extrahepatic biliary luminal epithelium in cholangiopathies is poorly understood. Prominin-1 (Prom1) is a key component of epithelial ciliary body of stem/progenitor cells. Given that intrahepatic Prom1-expressing progenitor cells undergo cholangiocyte differentiation, we hypothesized that Prom1 may promote restitution of the extrahepatic bile duct (EHBD) epithelium following injury. Utilizing various murine biliary injury models, we identified Prom1-expressing cells in the peribiliary glands (PBGs) of the EHBD. These Prom1-expressing cells are progenitor cells which give rise to cholangiocytes as part of the normal maintenance of the EHBD epithelium. Following injury, these cells proliferate significantly more rapidly to re-populate the biliary luminal epithelium. Null mutation of Prom1 leads to significantly more than ten-fold dilated PBGs following rhesus rotavirus-mediated biliary injury. Cultured organoids derived from Prom1 knockout mice are comprised of biliary progenitor cells with altered apical-basal cellular polarity, significantly fewer and shorter cilia, and decreased organoid proliferation dynamics consistent with impaired cell motility. We, therefore, conclude that Prom1 is involved in biliary epithelial restitution following biliary injury in part through its role in supporting cell polarity.
2022-12-05 | GSE220054 | GEO
Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05).
2012-12-13 | GSE16696 | GEO