MIMIC: An interconnected multiorgan platform to recreate the complex pathophysiology of the Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a leading cause of chronic liver disease, posing significant health and economic challenges. One in 5 people in the UK are estimated to be affected by MASLD, and in 2019, the total global cost of MASLD and its complications—such as cirrhosis, and liver cancer—was estimated at $1 trillion. MASLD is considered a multi-system disease and results from a complex interplay between metabolic processes involving lipid metabolism, synergy between excess weight and liver damage, abnormal insulin signalling, inflammatory responses, and alterations in gut health, all of which are influenced by the genetic makeup of individual patients. This complexity makes MASLD a difficult disease to understand and treat. The absence of reliable human-relevant models that replicate the multifaceted nature of MASLD has hindered the development and testing of effective treatments. Recent studies show that most animal models fail to adequately represent key features of MASLD in humans, underscoring the urgent need for more accurate human-based models. This gap has spurred growing interest in the development of tissue models in the lab. However, challenges persist, such as unreliable cell sources, the lack of immune system functionality in these models, limited reproducibility, and difficulties in capturing the full complexity of the disease, including organ interactions and patient-specific factors like genetics. Our proposal aims to address these challenges by using peripheral blood cells from well-characterised men and women with MASLD to differentiate pluripotent stem cells. These stem cells will be used to develop immunocompetent models of three key organs involved in MASLD: the gut, liver, and adipose tissue. These organ micro-tissues developed using cells from the same individual (a unique advantage of using pluripotent stem cells) will be housed in small bioreactors that recreate their natural environments and facilitate the connection between them, mimicking their interactions within the human body. By studying these interconnected tissue models, we aim to explore how the gut, liver, and fat tissues interact in the development of liver fibrosis in MASLD and evaluate potential treatments. We will utilise cells from patients with MASLD of Caucasian and South Asian descent, who exhibit distinct disease presentations and divergent treatment responses. This will allow us to benchmark our model against clinical data, representing a critical step toward validating these in vitro models for academic and industrial drug discovery and testing. We believe that incorporating both the metabolic and inflammatory aspects of MASLD will allow for a more accurate representation of disease pathology, including the modelling of liver fibrosis—a key feature that current models do not replicate. Furthermore, we hypothesise that models derived from patients with different ancestries and genetic backgrounds will exhibit varied responses to treatments, mirroring real-world patient outcomes. Demonstrating these differences will enhance the credibility of this new disease model, fostering its adoption by researchers, clinicians, and the pharmaceutical industry in the investigation of MASLD pathophysiology and the development of novel therapies. This project builds on our expertise in scalable culture methods, stem cell-based organ models, organ-on-chip technology, clinical hepatology, and drug discovery. The platform we develop will be a valuable resource for researchers, industry professionals, and clinicians working on complex diseases, and aligns with emerging regulations such as the FDA Modernization Act, which supports the use of organ-on-chip models to replace animal testing.