Induction of MASH in Three-Dimensional Bioprinted Human Liver Tissue
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PROVIDER: PRJNA1178128 | ENA |
REPOSITORIES: ENA
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Project description:Non-alcoholic steatohepatitis (NASH) represents a significant and growing public health concern worldwide, characterized by hepatic steatosis, inflammation, and varying degrees of fibrosis. In vitro models of NASH play a crucial role in elucidating the underlying mechanisms of disease pathogenesis, identifying potential therapeutic targets, and evaluating the efficacy of pharmacological interventions. Several preclinical models of MASH have been developed and are being used extensively to study these areas. While standard cell culture models allow for elucidation of certain molecular pathways involved in MASH pathogenesis, they lack three-dimensional architecture and cellular heterogeneity observed in native liver tissue, potentially limiting their physiological relevance and inability to fully capture the multifactorial nature of the disease Precision cut liver slices from MASH livers retain the complex multicellular architecture of the liver including hepatocyte arrangement, sinusoidal structure, and cellular interactions, but the metabolism deteriorates over a short period of time (usually reported as 2 days). Human liver organoids from iPSCs (induced pluripotent stem cells) retain the genetics of the patients but fail to fully differentiate into hepatocytes or have the liver architecture. Human liver spheroids incubated in a MASH cocktail develop several phenotypic characteristics of a MASH liver, but the small spheroid size precludes extensive histological comparisons to MASH livers. Microphysiological systems (MPS) or “liver on a chip” in which 3D cultures are perfused, maintain many of the physiological functions of the liver owing to precise control over microenvironmental parameters, including fluid flow, nutrient gradients, and mechanical cues. However, MPS are difficult to scale up and have not been developed to reproduce a MASH phenotype. In comparison, bioprinted liver tissues for MASH have many advantages. Organovo’s 3D bioprinted liver tissues are comprised of all major primary liver cells including hepatocytes, endothelial cells, stellates and Kupffer cells, mixed in physiologically relevant ratios. These cells are then bioprinted in precise pre-defined liver specific geometries to recapitulate complexity of the hepatic microenvironment.. This mimicking of tissue architecture enables more accurate representation of cellular interactions, spatial organization, and microenvironmental cues crucial for MASH pathogenesis. The liver tissues developed using this method maintain differentiation and metabolism over several weeks. In this paper, we further demonstrated that upon treatment with a MASH induction cocktail, these liver tissues respond accurately by developing steatosis and fibrosis Tissue response varies depending in response to the complexity of the MASH cocktail.
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Project description:Reliable non-invasive tools to diagnose at risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high risk MASH patients (NAFLD Activity Score (NAS) >4 and fibrosis score >2). In this three-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease (MASLD), we first developed a multi-protein predictor for discriminating NAS>4 based on SOMAscan proteomics quantifying 1,305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N=168), and enhanced by adding clinical variables to create the 9-feature MASH Dx Score which predicted MASH and also high risk MASH (F2+). The MASH Dx Score was validated in two independent, external cohorts from Germany (N=139) and Brazil (N=177). The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of four proteins (THBS2, GDF15, SELE, IGFBP7) was verified by ELISA in the expanded discovery and independently in the two external cohorts. MASH Dx Score incorporated these proteins with established MASH risk factors (age, BMI, ALT, diabetes, hypertension) to achieve good discrimination between MASH and MASLD without MASH (AUC:0.87- discovery; 0.83- pooled external validation cohorts), with similar performance when evaluating high risk MASH F2-4 (vs. MASH F0-1 and MASLD without MASH). The MASH Dx Score offers the first reliable non-invasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high risk MASH in patient cohorts from the US, Brasil and Europe.
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