PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.

Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling.

Revolutionizing Drug Discovery: The Impact of Distinct Designs and Biosensor Integration in Microfluidics-Based Organ-on-a-Chip Technology.

Traditional drug development is a long and expensive process with high rates of failure. This has prompted the pharmaceutical industry to seek more efficient drug development frameworks, driving the emergence of organ-on-a-chip (OOC) based on microfluidic technologies. Unlike traditional animal experiments, OOC systems provide a more accurate simulation of human organ microenvironments and physiological responses, therefore offering a cost-effective and efficient platform for biomedical research, particularly in the development of new medicines.

Screening a Compound Library to Identify Additives That Boost Cytochrome P450 Enzyme Function in Vascularised Liver Spheres.

To accurately study human organ function and disease 'in the dish', it is necessary to develop reliable cell-based models that closely track human physiology. Our interest lay with the liver, which is the largest solid organ in the body. The liver is a multifunctional and highly regenerative organ; however, severe liver damage can have dire consequences for human health.

Chemically programmed metabolism drives a superior cell fitness for cartilage regeneration.

The rapid advancement of cell therapies underscores the importance of understanding fundamental cellular attributes. Among these, cell fitness-how transplanted cells adapt to new microenvironments and maintain functional stability in vivo-is crucial. This study identifies a chemical compound, FPH2, that enhances the fitness of human chondrocytes and the repair of articular cartilage, which is typically nonregenerative.

Early interferon lambda production is induced by double-stranded RNA in iPS-derived hepatocyte-like cells.

Hepatotropic viruses are amongst the most ubiquitous pathogens worldwide, causing significant morbidity and mortality. As hepatocytes are among the primary targets of these viruses, their ability to mount early effective innate defence responses is of major research interest. Interferon lambda (IFNL) is produced early in response to viral stimulation in other cell types, but hepatocyte production of this interferon is little investigated.

Bioengineering vascularized liver tissue for biomedical research and application.

The liver performs a wide range of biological functions that are essential to body homeostasis. Damage to liver tissue can result in reduced organ function, and if chronic in nature can lead to organ scarring and progressive disease. Currently, donor liver transplantation is the only longterm treatment for end-stage liver disease.

In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study.

Background: Perfluoroalkyl and polyfluoroalkyl substances are classed as endocrine disrupting compounds but continue to be used in many products such as firefighting foams, flame retardants, utensil coatings, and waterproofing of food packaging. Perfluoroalkyl exposure aberrantly modulates lipid, metabolite, and bile acid levels, increasing susceptibility to onset and severity of metabolic diseases, such as diabetes and metabolic dysfunction-associated steatotic liver disease. To date, most studies in humans have focused on perfluoroalkyl-exposure effects in adults.

XBP1 as a novel molecular target to attenuate drug resistance in hepatocellular carcinoma.

Introduction: Despite improvements in clinical management of hepatocellular carcinoma (HCC), prognosis remains poor with a 5-year survival rate less than 40%. Drug resistance in HCC makes it challenging to treat; therefore, it is imperative to develop new therapeutic strategies. Higher expression of X-box binding protein 1 (XBP1) in tumor cells is highly correlated with poor prognosis.

The Influence of Sex Hormones in Liver Function and Disease.

The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology in health and disease. A major risk factor for the development of liver disease is hepatic fibrosis.

Chemically cross-linked hydrogels from repetitive protein arrays.

Biomaterials for tissue regeneration must mimic the biophysical properties of the native physiological environment. A protein engineering approach allows the generation of protein hydrogels with specific and customised biophysical properties designed to suit a particular physiological environment. Herein, repetitive engineered proteins were successfully designed to form covalent molecular networks with defined physical characteristics able to sustain cell phenotype.

Serum-Free Production of Human Stem Cell-Derived Liver Spheres for Cancer Metastasis Research.

Renewable and scalable human liver tissue platforms are a powerful tool to study organ physiology and model diseases, such as cancer. Stem cell-derived models provide an alternative to cell lines, which can display limited relevance to primary cells and tissue. Historically, two-dimensional (2D) cultures have been used to model liver biology as they are easy to scale and deploy.

Identification of an FXR-modulated liver-intestine hybrid state in iPSC-derived hepatocyte-like cells.

Background & Aims: Pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLC) have enormous potential as a replacement for primary hepatocytes in drug screening, toxicology and cell replacement therapy, but their genome-wide expression patterns differ strongly from primary human hepatocytes (PHH).

Methods: We differentiated human induced pluripotent stem cells (hiPSC) via definitive endoderm to HLC and characterized the cells by single-cell and bulk RNA-seq, with complementary epigenetic analyses. We then compared HLC to PHH and publicly available data on human fetal hepatocytes (FH) ex vivo; we performed bioinformatics-guided interventions to improve HLC differentiation via lentiviral transduction of the nuclear receptor FXR and agonist exposure.

Nuclear factor programming improves stem-cell-derived hepatocyte phenotype.

In this issue of Cell Stem Cell, Ma et al. demonstrate that the activation of the nuclear receptor thyroid hormone receptor beta (NR1A2) improves the differentiation status of hepatocyte-like cells derived from human pluripotent stem cells.

Maternal over-the-counter analgesics use during pregnancy and adverse perinatal outcomes: cohort study of 151 141 singleton pregnancies.

Objectives: To identify any associations between in utero exposure to five over-the-counter (non-prescription) analgesics (paracetamol, ibuprofen, aspirin, diclofenac, naproxen) and adverse neonatal outcomes.

Design: Retrospective cohort study using the Aberdeen Maternity and Neonatal Databank.

Participants: 151 141 singleton pregnancies between 1985 and 2015.

Pluripotent Stem Cell-Derived Hepatocytes Inhibit T Cell Proliferation through Tryptophan Starvation.

Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, whether of embryonic origin or induced via the reprogramming of somatic cells, are of considerable therapeutic interest in the regenerative medicine field. However, regardless of the cell type, host immune responses present a barrier to success.

Serum-Free Production of Three-Dimensional Hepatospheres from Pluripotent Stem Cells.

Developing renewable human liver tissue from stem cells has been pursued as a potential source of biological material for pharmaceutical and clinical endeavors. At present, two-dimensional differentiation procedures deliver tissue lacking long-term phenotypic and functional stability. Efforts to overcome these limiting factors have led to the development of protocols to generate three-dimensional cellular aggregates.

Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure.

Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease.

Protocol for automated production of human stem cell derived liver spheres.

This protocol describes how to produce human liver spheres from pluripotent stem cell-derived hepatic progenitors, endothelial cells, and hepatic stellate cells. Liver spheres form by self-assembly in microwells, generating up to 73 spheres per well of a 96-well plate. This process was automated using liquid handling and pipetting systems, permitting cost-effective scale-up and reducing sphere variability.

Modeling human hepatic steatosis in pluripotent stem cell-derived hepatocytes.

This protocol describes the production of hepatocyte-like cells (HLCs) from human pluripotent stem cells and how to induce hepatic steatosis, a condition characterized by intracellular lipid accumulation. Following differentiation to an HLC phenotype, intracellular lipid accumulation is induced with a steatosis induction cocktail, allowing the user to examine the cellular processes that underpin hepatic steatosis. Furthermore, the renewable nature of our system, on a defined genetic background, permits in-depth mechanistic analysis, which may facilitate therapeutic target identification in the future.

Mathematical modelling of oxygen gradients in stem cell-derived liver tissue.

A major bottleneck in the study of human liver physiology is the provision of stable liver tissue in sufficient quantity. As a result, current approaches to modelling human drug efficacy and toxicity rely heavily on immortalized human and animal cell lines. These models are informative but do possess significant drawbacks.

A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term encompasses a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis, which have, to date, been challenging to model in the laboratory setting. Here, we present a human pluripotent stem cell (hPSC)-derived model of hepatic steatosis, which overcomes inherent challenges of current models and provides insights into the metabolic rewiring associated with steatosis.