A5069811614- Liver physiology and pathology
- Pluripotent Stem Cells Research
- Pancreatic function and diabetes
- Liver Disease Diagnosis and Treatment
- Drug-Induced Hepatotoxicity and Protection
- Mesenchymal stem cell research
- Immunotherapy and Immune Responses
- 3D Printing in Biomedical Research
- CRISPR and Genetic Engineering
- Angiogenesis and VEGF in Cancer
- Organ Transplantation Techniques and Outcomes
- CAR-T cell therapy research
- Zebrafish Biomedical Research Applications
- T-cell and B-cell Immunology
- Renal and related cancers
- Tissue Engineering and Regenerative Medicine
- COVID-19 Clinical Research Studies
- Cholangiocarcinoma and Gallbladder Cancer Studies
- DNA Repair Mechanisms
- Liver Disease and Transplantation
- Drug Transport and Resistance Mechanisms
- Immune Response and Inflammation
- Cell death mechanisms and regulation
- Diet and metabolism studies
- Neonatal Respiratory Health Research
Scottish National Blood Transfusion Service
2014-2024
Icahn School of Medicine at Mount Sinai
2024
University of Edinburgh
2007-2020
Centre for Inflammation Research
2020
MRC Centre for Regenerative Medicine
2007-2015
University of Oxford
2012
Swansea University
2012
Gower College Swansea
2012
Sree Balaji Dental College and Hospital
2011
Medical Research Council
2008-2010
With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled direct differentiation lineage, such as hepatic endoderm (HE), would revolutionize way we study human liver biology and efficient “off shelf” models disease. Here, show “proof concept” that iPSC lines representing both male female sexes two ethnic origins can be differentiated HE at efficiencies between 70%–90%, using method mimicking...
Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. To date, however, their homogeneous cellular differentiation to specific cell types in vitro has proven difficult. Wnt signaling been shown play important roles coordinating development, and we demonstrate that Wnt3a is differentially expressed at critical stages human liver development vivo. The essential role hepatocyte from hESCs paralleled by our model, demonstrating the importance physiologic...
Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and refractory to surgical intervention chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward development treatments for this cancer. Here we utilized human tissue; CC cell xenografts; p53-deficient transgenic mouse model; non-transgenic, chemically induced rat model that accurately reflects both inflammatory regenerative background associated with pathology. Using these...
<h3>Background</h3> Stem/progenitor cell niches in tissues regulate stem/progenitor differentiation and proliferation through local signalling. <h3>Objective</h3> To examine the composition formation of stem progenitor niches. <h3>Methods</h3> The hepatic niche independent models liver injury activation rodents humans was studied. identify origin cells, sex-mismatched bone marrow transplants mice, who had received choline–ethionine-deficient-diet to induce activation, were used. matrix...
A decade of research has sought to identify circulating endothelial progenitor cells (EPC) in order harness their potential for cardiovascular regeneration. Endothelial outgrowth (EOC) most closely fulfil the criteria an EPC, but origin remains obscure. Our aim was source and precursor EOC assess regenerative compared mature cells. are readily isolated from umbilical cord blood (6/6 donors) peripheral mononuclear (4/6 not bone marrow (0/6) or following mobilization with granulocyte-colony...
There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for Wilms' tumour gene, Wt1, lack kidneys, gonads, spleen die at mid-gestation due defective coronary vasculature. Wt1 vital maintaining mesenchymal–epithelial balance these tissues required epithelial-to-mesenchyme transition (EMT) generates vascular progenitors. Although only expressed rare cell populations adults including...
Abstract The study of the role apoptosis in thymocyte development has been hampered by lack a means directly immunophenotyping cells undergoing early phase apoptosis. This restriction overcome single laser flow cytometry which is detected Ethidium Bromide (EBr) staining and cell phenotype binding FITC‐labelled antibody. initial observed as population that stains faintly with EBr preceding characteristically bright EBrstaining normally associated death. Here we demonstrate using CD4 + CD8 CD3...
Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary hepatocytes (PHHs). Limited availability, interdonor functional variability and early phenotypic alterations PHHs restrict their use, whilst such as HepG2 lack a substantial variable set liver-specific functions CYP450 activity. Alternatives include HepG2-derivative C3A cells selected more differentiated metabolically active phenotype. Human HepaRG an...
Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) 4 (p4) produced proregenerative factors, strongly suppressing T cell responses the...
Recent work has indicated that adult bone marrow-derived cells have the ability to contribute both haematopoietic system and other organs. Haematopoietic reconstitution by whole marrow selected but not fully characterised cell populations resulted in reports indicating high-level repopulation of lung epithelia. The well-characterised from side population a robust for reconstitution. We used freshly isolated derived ROSA26 demonstrate despite being unable embryos following blastocyst...
DNA ligase I is the key for replication in mammalian cells and has also been reported to be involved a number of recombination repair processes. Our previous finding that Lig1 knockout mouse embryos developed normally mid-term before succumbing specific haematopoietic defect was difficult reconcile with report essential viability cultured cells. To address this issue, we generated second targeted allele found phenotypes our two mutant lines are identical. Widely different levels fusion...
Summary Twenty‐two patients with acute myeloid leukaemia were recruited into a phase I/II clinical trial investigating the vaccination of in complete remission (CR) autologous dendritic‐like cells (DLLC). At entry, harvested and tested for their ability to undergo cytokine‐induced dendritic cell differentiation. Patients then treated intensive chemotherapy. Five achieved both CR had that successfully underwent differentiation therefore proceeded vaccination. Four escalating doses DLLC...
Abstract Organotypic liver culture models for hepatotoxicity studies that mimic in vivo hepatic functionality could help facilitate improved strategies early safety risk assessment during drug development. Interspecies differences sensitivity and mechanistic profiles, low predictive capacity limitations of conventional monocultures human hepatocytes, with high attrition rates remain major challenges. Herein, we show stable, cell-type specific phenotype/cellular polarity differentiated...
Dendritic cells (DC) are specialized sentinel that bridge the innate and adaptive immune response play a crucial role in shaping response. Vitamin D, known epidemiological risk factor for development of several autoimmune diseases, influences dendritic cells. Consequently, vitamin D metabolites frequently used protocols to develop therapeutic cell therapies diseases. However, mechanisms by which modulates DC function remain poorly understood. We investigated effects on murine CD11c+ bone...
Chlorpromazine (CPZ) is a neuroleptic drug and prototype compound used to study intrahepatic cholestasis. The exact mechanisms of CPZ induced cholestasis remain unclear. Rat hepatocytes, or sandwich culture rat human have been the most commonly models for studying toxicity in vitro. However, better predict outcomes pre-clinical trials where may be an unwanted consequence, vitro model, based on HepaRG cells, capable real-time, non-invasive label free monitoring, alongside molecular...
The stem cell factor (SCF)-KIT signal transduction pathway plays a role in the proliferation, differentiation and survival of range progenitor types but little is known about its function embryonic (ES) cells. We generated ES cells carrying null allele Kit as well knock-in that encodes an SCF-independent hybrid KIT receptor can be activated by FKBP binding drug, AP20187. die when induced to differentiate upon withdrawal leukaemia inhibitory monolayer culture. This phenotype recapitulated...
Human embryonic stem cells (hESCs) offer an inexhaustible supply of human somatic cell types through their ability to self-renew while retaining pluripotency. As such, hESC-derived are important for applications ranging from in vitro modeling therapeutic use. However, full potential be realized, both the growth undifferentiated and derivatives must performed defined culture conditions. Many research groups maintain hESCs using mouse fibroblasts (MEF) MEF conditioned medium (CM). The use...
11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective inhibitor or crossed 11β-HSD1-KO to generate double knockouts (DKOs) challenged an...
Abstract Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming blood-biliary barrier. In acetaminophen-hepatotoxicity, mechanism which tissue cohesion and are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts integrity TJ cell-matrix adhesions, with indicators stress liver injury human hepatic...
Background: Human embryonic stem cells (hESCs) can be efficiently differentiated to hepatocyte-like (HLCs) in vitro and demonstrate many of the functions gene expression found adult liver. Aims: In this study, we assess therapeutic value HLCs long-term cell-based therapies vivo. Methods: hESC-derived were injected into spleen acutely injured NODscidIL-2Rγnull mice analysed at various time points post-transplantation up 3 months. Results: Large clusters human engrafted after days had expanded...
Endothelial progenitor cells (EPC) capable of initiating or augmenting vascular growth were recently identified within the small population CD34-expressing that circulate in human peripheral blood and which are considered hematopoietic (HPC). Soon thereafter HPC began to be used clinical trials as putative sources EPC for therapeutic regeneration, especially myocardial critical limb ischemias. However, unlike where efficacy is related quantitatively CD34+ cell numbers implanted, there has...