A5087005461- Liver physiology and pathology
- Retinal Development and Disorders
- Pluripotent Stem Cells Research
- Photoreceptor and optogenetics research
- Renal and related cancers
- Neuroscience and Neural Engineering
- CRISPR and Genetic Engineering
- Insect Resistance and Genetics
- 3D Printing in Biomedical Research
- Protease and Inhibitor Mechanisms
- Phytase and its Applications
- Photochromic and Fluorescence Chemistry
- Pancreatic and Hepatic Oncology Research
- Pancreatic function and diabetes
- Genetic factors in colorectal cancer
- Clinical Nutrition and Gastroenterology
- RNA regulation and disease
- RNA Research and Splicing
- Pediatric Hepatobiliary Diseases and Treatments
- Childhood Cancer Survivors' Quality of Life
- bioluminescence and chemiluminescence research
- RNA modifications and cancer
- Virus-based gene therapy research
- Lysosomal Storage Disorders Research
- Drug Transport and Resistance Mechanisms
Imperial College London
2021-2024
King's College London
2018-2022
NIHR Imperial Biomedical Research Centre
2022
Cell and Gene Therapy Catapult
2022
Guy's Hospital
2019
Wake Forest University
2019
Forest Institute
2019
Charlottesville Medical Research
2019
John Wiley & Sons (United States)
2019
University College London
2013-2018
Transplantation of rod photoreceptors, derived either from neonatal retinae or pluripotent stem cells (PSCs), can restore rod-mediated visual function in murine models inherited blindness. However, humans depend more upon cone photoreceptors that are required for daylight, color, and high-acuity vision. Indeed, macular retinopathies involving loss cones leading causes An essential step developing cell-based therapies maculopathies is the ability to generate transplantable human renewable...
Generation of human organoids from induced pluripotent stem cells (iPSCs) offers exciting possibilities for developmental biology, disease modelling and cell therapy. Significant advances towards those goals have been hampered by dependence on animal derived matrices (e.g. Matrigel), immortalized lines resultant structures that are difficult to control or scale. To address these challenges, we aimed develop a fully defined liver organoid platform using inverted colloid crystal (ICC) whose...
Abstract The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin human parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report existence a hepatobiliary hybrid progenitor (HHyP) population in foetal using single-cell RNA sequencing. HHyPs are anatomically restricted to ductal plate maintain transcriptional profile distinct from hepatocytes, mature BECs. In addition,...
Abstract Loss of photoreceptors due to retinal degeneration is a major cause untreatable blindness. Cell replacement therapy, using pluripotent stem cell-derived photoreceptor cells, may be feasible future treatment. Achieving safe and effective cell critically dependent on the stringent selection purification optimal cells for transplantation. Previously, we demonstrated transplantation post-mitotic precursor labelled by fluorescent reporter genes. As genetically are not desirable here...
Highlights•Transplanted cone photoreceptors can incorporate into host retina•Transplanted undergo material transfer with photoreceptors•Host retinas disrupted cytoarchitecture facilitate incorporation•Host environment affects relative contributions of integration and transferSummaryHuman vision relies heavily upon photoreceptors, their loss results in permanent visual impairment. Transplantation healthy restore function models inherited blindness, a process previously understood to arise by...
The loss of cone photoreceptors that mediate daylight vision represents a leading cause blindness, for which cell replacement by transplantation offers promising treatment strategy. Here, we characterize differentiation in retinas derived from mouse embryonic stem cells (mESCs). Similar to vivo development, temporal pattern progenitor marker expression is followed the early thyroid hormone receptor β2-positive precursors and, subsequently, exhibiting cone-specific phototransduction-related...
Adeno-associated viral vectors are showing great promise as gene therapy for a wide range of retinal disorders. To date, evaluation therapeutic approaches has depended almost exclusively on the use animal models. With recent advances in human stem cell technology, cell-derived retina now offers possibility to assess efficacy organoids vitro. Here we test six adeno-associated virus (AAV) serotypes [AAV2/2, AAV2/9, AAV2/8, AAV2/8T(Y733F), AAV2/5, and ShH10] determine their efficiency...
Abstract Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC-Heps) afford tremendous possibilities for treatment patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite such applications but have only recently been established. Whether cGMP capable hepatic differentiation is not known. To address this knowledge gap, we examined proficiency three derived (two hiPSC and one hESC) to...
Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and regulation gene expression in eukaryotic cells. While defects pre-mRNA have been implicated a number diseases their involvement metabolic pathologies still unclear. Here, we show that both alternative splicing polyadenylation, two major steps processing, are significantly altered non-alcoholic fatty liver disease (NAFLD). Moreover, find Serine Arginine Rich Splicing Factor 10 (SRSF10) binding enriched...
Human pluripotent stem cell-derived hepatocytes (hPSC-Heps) may be suitable for treating liver diseases, but differentiation protocols often fail to yield adult-like cells. We hypothesised that replicating healthy niche biochemical and biophysical cues would produce with desired metabolic functionality. Using 2D synthetic hydrogels which independently control mechanical properties cues, we found culturing hPSC-Heps on surfaces matching the stiffness of fibrotic tissue upregulated expression...
The truncating mutations in tight junction protein 2 (TJP2) cause progressive cholestasis, liver failure, and hepatocyte carcinogenesis. Due to the lack of effective model systems, there are no targeted medications for pathology with TJP2 deficiency. We leveraged technologies patient-specific induced pluripotent stem cells (iPSC) CRISPR genome-editing, we aim establish a disease which recapitulates phenotypes patients
Intra-peritoneal placement of alginate encapsulated human induced pluripotent stem cell-derived hepatocytes (hPSC-Heps) represents a potential new bridging therapy for acute liver failure. One the rate-limiting steps that needs to be overcome make such procedure more efficacious and safer is reduce accumulation fibrotic tissue around cells allow free passage relevant molecules in out metabolism. Novel chemical compositions afford possibility achieving this aim. We accordingly used sulfated...
Primary hepatocyte transplantation (HTx) is a safe cell therapy for patients with liver disease, but wider application circumvented by poor engraftment due to limitations in quality and strategies. Hepatocyte-like cells (HLCs) derived from human induced pluripotent stem (hiPSC) are considered promising alternative also require optimisation of often transplanted prior full maturation. Whole-body vivo imaging would be highly beneficial assess non-invasively monitor the short long-term. Here we...
Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of serpin family A member 1 "Z" genetic variant driving alpha-1 (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease.
Exfoliative dermatitis and erythroderma in infancy are rare. Clinicians need to be alert the possible diagnosis of Omenn's syndrome (OS), a rare form combined immunodeficiency infants presenting with exfoliative dermatitis, erythroderma, recurrent infections, eosinophilia raised IgE. OS is fatal unless treated by bone-marrow transplantation (BMT). We describe 3-week-old girl who presented widespread scaly erythematous rash stomatitis, was initially for presumed atopic eczema primary herpes...
Abstract The liver is largely composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists as to whether a stem/progenitor cell capable renewing both BECs exists. Single RNA sequencing freshly isolated human foetal healthy adult identified hepatocyte, hepatoblast progenitor (hLPC) populations. hLPCs, found at the interface between ducts in tissue, were distinguishable from by their negative expression TROP-2. Prospective isolation followed vitro culture demonstrated...
Abstract Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC-Heps) afford tremendous possibilities for treatment patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite such applications but have only recently been established. Whether cGMP capable hepatic differentiation is not known. To address this knowledge gap, we examined proficiency three derived (two hiPSC and one hESC) to...
Abstract Generation of human organoids from induced pluripotent stem cells (iPSCs) offers exciting possibilities for developmental biology, disease modelling and cell therapy. Significant advances towards those goals have been hampered by dependence on animal derived matrices (e.g. Matrigel), immortalized lines resultant structures that are difficult to control or scale. To address these challenges, we aimed develop a fully defined liver organoid platform using inverted colloid crystal (ICC)...
Abstract Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by inheritance of the SERPINA1-Z genetic variant (PiZ) leading to protein misfolding and liver toxicity. There remain no approved medicines for this disease. Here we report results small molecule screen performed in patient-derived iPSC hepatocytes that identified Leucine-rich repeat kinase-2 (LRRK2), as potentially new therapeutic target. Genetic deletion LRRK2 PiZ mice reduced both intrahepatic misfolded...
Abstract Alpha-1 antitrypsin deficiency is a life-threatening condition caused by inheritance of the SERPINA1 gene ‘Z’ variant. This single base pair mutation leads to protein misfolding, ER entrapment and gain toxic function. Despite significant unmet medical need presented this disorder, there remain no approved medicines only curative option liver transplantation. We hypothesized that an unbiased screen human hepatocytes harbouring Z (ATZ) using small molecules targeted against...