A5019878734- Liver physiology and pathology
- Organ Transplantation Techniques and Outcomes
- Pediatric Hepatobiliary Diseases and Treatments
- Pancreatic function and diabetes
- Liver Disease Diagnosis and Treatment
- Liver Diseases and Immunity
- Galectins and Cancer Biology
- Telomeres, Telomerase, and Senescence
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Ferroptosis and cancer prognosis
- Cancer-related molecular mechanisms research
- Cancer Research and Treatments
- Wnt/β-catenin signaling in development and cancer
- Gallbladder and Bile Duct Disorders
- Mesenchymal stem cell research
- RNA Interference and Gene Delivery
- Renal and related cancers
- Immune cells in cancer
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related gene regulation
- Tissue Engineering and Regenerative Medicine
- Clinical Nutrition and Gastroenterology
- Immune Cell Function and Interaction
- Phagocytosis and Immune Regulation
- Ovarian cancer diagnosis and treatment
University of Edinburgh
2015-2025
Chongqing Medical University
2022-2025
Centre for Inflammation Research
2013-2025
Queen's Medical Centre
2022-2023
University of Birmingham
2018-2022
The Queen's Medical Research Institute
2013-2022
Erasmus MC
2021
Medical Research Council
2013-2020
MRC Centre for Regenerative Medicine
2013-2020
NIHR Birmingham Liver Biomedical Research Unit
2018
Inhibiting acute injury–induced senescence mediated by TGFβ signaling in regenerative epithelium improves liver regeneration.
Hepatocyte transplantation has shown promise for genetic diseases of the hepatocytes but to date limited efficacy non-genetic forms severe liver injury. Limited cell engraftment and poor function donor in recipient livers impacts clinical utility hepatocyte therapy. The mechanisms underpinning this are poorly understood. We explored a injury model, where predictable levels senescence was induced AhCreMdm2
Tissue progenitor cells are an attractive target for regenerative therapy. In various organs, bone marrow cell (BMC) therapy has shown promising preliminary results, but to date no definite mechanism been demonstrated account the observed benefit in organ regeneration. injury and regeneration is invariably accompanied by macrophage infiltration, their influence upon incompletely understood, direct signaling pathways may be obscured multiple roles of macrophages during injury. We therefore...
Abstract We describe a novel therapeutic approach for cirrhosis using mesenchymal stem cells (MSCs) and colony-stimulating factor-1-induced bone marrow-derived macrophages (id-BMMs) analyze the mechanisms underlying fibrosis improvement regeneration. Mouse MSCs id-BMMs were cultured from mouse marrow their interactions analyzed in vitro. MSCs, id-BMMs, combination therapy administered to mice with CCl4-induced cirrhosis. Fibrosis regression, liver regeneration, liver-migrating host...
Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression prevent undesired proliferation. However, under pathological circumstances, can adversely affect organ function, viability and regeneration. We have developed mouse model of biliary senescence, based on the conditional deletion Mdm2 in bile ducts control Krt19 promoter, exhibits features disease. Here we report senescent cholangiocytes induce profound alterations cellular signalling...
Liver regeneration after injury is normally mediated by proliferation of hepatocytes, although recent studies have suggested biliary epithelial cells (BECs) can differentiate into hepatocytes during severe liver when hepatocyte impaired. We investigated the effect hepatocyte‐specific β‐catenin deletion in recovery from and BEC‐to‐hepatocyte differentiation. To induce injury, we administered choline‐deficient, ethionine‐supplemented (CDE) diet to three different mouse models, first being mice...
Fibroproliferative diseases are driven by dysregulated tissue repair responses and a major cause of morbidity mortality because they affect nearly every organ system. Type 2 cytokine critically involved in repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis not well understood. Here, we have shown type effector interleukin-13 simultaneously, yet independently, directed hepatic compensatory proliferation hepatocytes biliary cells progressive...
Background and Aims Organoids provide a powerful system to study epithelia in vitro . Recently, this approach was applied successfully the biliary tree, series of ductular tissues responsible for drainage bile pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic ducts; EHBDs) or inside liver (intrahepatic IHBDs). These share many characteristics, including expression cholangiocyte markers such as keratin (KRT) 19. However,...
Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except transplantation. New therapies urgently required. We have therefore purified human epithelial cells (hBECs) from livers that were not used hBECs tested as a cell therapy in mouse model of which the conditional deletion Mdm2 cholangiocytes causes senescence, strictures, fibrosis. expandable phenotypically stable help restore...
Significance Clinical outcomes in cholangiocarcinoma (CC) are poor; few patients candidates for curative resection, and palliative chemotherapy produces only modest effects on survival. With an increasing incidence, new targets urgently needed. Notch has been identified as having potential to induce CC when transgenically overexpressed, this study aimed characterize how endogenous might drive tumorigenesis. We identify the atypical receptor Notch3 differentially overactivated CCs humans,...
Primary human hepatocytes (PHHs) are an essential tool for modeling drug metabolism and liver disease. However, variable plating efficiencies, short lifespan in culture, resistance to genetic manipulation have limited their use. Here, we show that the pyrrolizidine alkaloid retrorsine improves PHH repopulation of chimeric mice on average 10-fold rescues ability even poorly plateable donor provide cells subsequent ex vivo cultures. These mouse-passaged (mp) cultures overcome marked...
The thymus medulla is a key site for immunoregulation and tolerance, its functional specialisation achieved through the complexity of medullary thymic epithelial cells (mTEC). While importance function clear, production maintenance mTEC diversity remains poorly understood. Here, using ontogenetic inducible fate-mapping approaches, we identify mTEC-restricted progenitors as cytokeratin19
Mechanisms underlying the repair of extrahepatic biliary tree (EHBT) after injury have been scarcely explored. The aims this study were to evaluate, by using a lineage tracing approach, contribution peribiliary gland (PBG) niche in regeneration EHBT damage and vivo vitro, signaling pathways involved.Bile duct was induced administration 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 14 days Krt19Cre TdTomatoLSL mice. Human stem/progenitor cells (BTSC) within PBGs isolated from...
In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between surrounding matrix; however, its role in development regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, produced by enzymes, ST8SiaII ST8SiaIV, weakens interactions. The polySia with...
Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate parenchyma. HPCs exist a niche composed of myofibroblasts, macrophages laminin matrix. Galectin-3 (Gal-3) β-galactoside-binding lectin that binds to expressed injured mice humans.We examined role Gal-3 HPC activation. activation was studied following dietary induced hepatocellular (choline-deficient...
Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by progressive loss of biliary tract architecture) continue to occur after transplantation, negatively affecting function and frequently leading graft retransplantation. To study biological effects organ preservation before we generated murine models that recapitulate procurement static cold storage. In these...
Notch signaling promotes progenitor cell proliferation but inhibits hepatocyte differentiation during liver repair.
Cholangiopathies such as Primary Sclerosing Cholangitis (PSC) cause damage to the bile ducts and fibrosis with no effective cure. A reduction impairment in function of regulatory T cells (Tregs) occurs PSC. Yet, it is currently unknown what consequence this has on duct regeneration. We investigate whether Tregs regulate regeneration dynamics turnover during injury. used transgenic Foxp3GFPDTR model mimic reduced infiltration liver injury showed that intrahepatic limits Fate mapping...