A5006457421- Liver Disease Diagnosis and Treatment
- Liver physiology and pathology
- Liver Disease and Transplantation
- Immune cells in cancer
- Single-cell and spatial transcriptomics
- Phagocytosis and Immune Regulation
- Liver Diseases and Immunity
- Organ Transplantation Techniques and Outcomes
- Diabetes and associated disorders
- Pregnancy-related medical research
- Pediatric Hepatobiliary Diseases and Treatments
- Endoplasmic Reticulum Stress and Disease
- Hepatitis C virus research
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Lipid metabolism and disorders
- Gallbladder and Bile Duct Disorders
- Drug-Induced Hepatotoxicity and Protection
- Hepatitis B Virus Studies
- Pregnancy and preeclampsia studies
- Renal and related cancers
- Pancreatitis Pathology and Treatment
- Alcohol Consumption and Health Effects
- Wnt/β-catenin signaling in development and cancer
- Hormonal Regulation and Hypertension
- Genetic Associations and Epidemiology
University of Edinburgh
2016-2025
Centre for Inflammation Research
2016-2025
Centre for Cellular and Molecular Biology
2024
Queen's Medical Centre
2011-2023
The Queen's Medical Research Institute
2012-2023
Edinburgh Royal Infirmary
2011-2023
MRC Centre for Regenerative Medicine
2011-2023
DELL (United States)
2022
Medical Research Council
2011-2020
Peter MacCallum Cancer Centre
2019
Although macrophages are widely recognized to have a profibrotic role in inflammation, we used highly tractable CCl 4 -induced model of reversible hepatic fibrosis identify and characterize the macrophage phenotype responsible for tissue remodeling: hitherto elusive restorative macrophage. This CD11B hi F4/80 int Ly-6C lo subset was most abundant livers during maximal resolution represented principle matrix metalloproteinase (MMP) -expressing subset. Depletion this population...
Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role monocytes and macrophages therefore controversial.To define the during lung fibrogenesis resolution, explore phenotype cells involved.We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF.Depletion reduced as measured collagen (P = 0.0079); score...
Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during thought to be functionally homogeneous population. Here, we use single-cell RNA sequencing deconvolve the mesenchyme healthy fibrotic mouse liver, revealing spatial zonation HSCs across lobule. Furthermore, show that partition into topographically diametric lobule regions, designated portal...
Clinical studies of bone marrow (BM) cell therapy for liver cirrhosis are under way but the mechanisms benefit remain undefined. Cells monocyte-macrophage lineage have key roles in development and resolution fibrosis. Therefore, we tested therapeutic effects these cells on murine Advanced fibrosis was induced female mice by chronic administration carbon tetrachloride. Unmanipulated, syngeneic macrophages, their specific BM precursors, or unfractionated were delivered during injury. Mediators...
Significance Statement The innate immune system is central to injury and repair in the kidney, but heterogeneity of myeloid cell subsets behind these processes unknown. Complementary technologies—including bulk tissue transcriptomics, integrated droplet– plate-based single-cell RNA sequencing, paired blood exchange—resolved a murine model reversible unilateral ureteric obstruction, creating atlas. identified novel could be targeted ameliorate or enhance repair, including an Arg1+ monocyte...
The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. gut-liver axis contributes NASH, but the mechanisms involved consequences for NASH-induced liver cancer remain unknown. We investigated role gastrointestinal B cells in development HCC.
Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding disease mechanisms, specific contribution metastatic microenvironment ADT remains largely unknown. The current study identified macrophage major microenvironmental component bone-metastatic patients. Using a novel vivo model, we demonstrated macrophages were critical for enzalutamide through induction...
Abstract The liver has a unique ability to regenerate 1,2 ; however, in the setting of acute failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency transplantation as only curative option 3–5 . Here, advance understanding human regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling healthy and ALF explant livers generate single-cell, pan-lineage atlas regeneration. We uncover novel ANXA2 + migratory hepatocyte subpopulation, which...
Elastin has been linked to maturity of liver fibrosis. To date, the regulation elastin secretion and its degradation in fibrosis not characterized. The aim this work was define accumulation role paradigm elastase macrophage metalloelastase (MMP-12) turnover during Liver induced by either intraperitoneal injections carbon tetrachloride (CCl(4) ) for up 12 weeks (rat mouse) or oral administration thioacetamide (TAA) 1 year (mouse). synthesis, deposition, were investigated immunohistochemistry,...
Liver fibrosis, and its end stage cirrhosis are a major cause of morbidity mortality therapeutic options limited. However, the traditional view liver disease as an irreversible process is obsolete it now evident that development fibrosis dynamic potentially bidirectional process. Spontaneous resolution scarring seen in animal models human trials which stimuli responsible for chronic or repeated hepatic inflammation successfully removed. Key players stellate cells, macrophages, MMPs their...
Does female ageing have a negative effect on the DNA repair capacity of oocytes fertilised by spermatozoa with controlled levels damage?Compared to from younger females, older females reduced damaged introduced spermatozoa.The reproductive lifespan in women declines age predominantly due poor oocyte quality. This leads decreased outcomes for undergoing assisted technology (ART) treatments, compared young women. Ageing and quality been clearly associated aneuploidy, but range factors that...
Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering complete MASLD severity spectrum, created secure, searchable, open resource (SteatoSITE). In 668 cases 39 controls, we generated hepatic bulk RNA...
Hepatic fibrosis is the common end point to chronic injury of varied aetiology. There now excellent evidence in both human studies and animal models that liver a bidirectional process with significant reversible component. The hepatic stellate cell (HSC), following activation myofibroblast phenotype, principal producing extracellular matrix (ECM) during fibrogenesis main source TIMP-1, which inhibits endogenous matrix-degrading activity metalloproteinases (MMPs), thus promoting scar...
Liver cirrhosis is a major cause of morbidity and mortality worldwide has very limited therapeutic options. Regardless the aetiology, hepatic fibrosis characteristic feature chronic liver disease. Our knowledge regarding pathogenesis this scarring grown exponentially in past 2S years. It now clear that highly dynamic process long-held dogma it irreversible relentlessly progressive being challenged. In review, we will summarise key pathogenic mechanisms at play focus on evidence demonstrating...
Summary Background The nonstructural 3 serine protease inhibitors ( PI s), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C HCV ) infection. When used combination with pegylated interferon ribavirin, these drugs greatly improve sustained virological response rates both treatment‐naïve patients who have had previous failure on treatment. However, addition agents will increase complexity therapeutic regimens,...
Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it not clear how its pathogen recognition phagocytic functions maintain homeostasis prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity alcohol-related Here, we demonstrate that reduced tissues...