Pump‐Less, Recirculating Organ‐on‐Chip (rOoC) Platform to Model the Metabolic Crosstalk between Islets and Liver

Abstract

Type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction‐associated steatotic liver disease (MASLD) are epidemiologically correlated disorders with a worldwide growing prevalence. While the mechanisms leading to the onset and development of these conditions are not fully understood, predictive tissue representations for studying the coordinated interactions between central organs that regulate energy metabolism, particularly the liver and pancreatic islets, are needed. Here, a dual pump‐less recirculating Organ‐on‐Chip (dual‐rOoC) platform that combines human pluripotent stem cell (sc)‐derived sc‐liver and sc‐islet organoids is presented. The platform reproduces key aspects of the metabolic cross‐talk between both organs, including glucose levels and selected hormones, and supports the viability and functionality of both sc‐islet and sc‐liver organoids while preserving a reduced release of pro‐inflammatory cytokines. In a model of metabolic disruption in response to treatment with high lipids and fructose, sc‐liver organoids exhibit hallmarks of steatosis and insulin resistance, while sc‐islets produce pro‐inflammatory cytokines on‐chip. Finally, the platform reproduces known effects of anti‐diabetic drugs on‐chip. Taken together, the platform provides a basis for functional studies of obesity, T2DM, and MASLD on‐chip, as well as for testing potential therapeutic interventions.This article is protected by copyright. All rights reserved

Cell identity dynamics and insight into insulin secretagogues when employing stem cell-derived islets for disease modeling

“…Our data revealed that palmitate amplifies insulin section in both human primary islets and SC-islets. To this end, the SC-islets would be suitable for obese modeling, and our previous work has evaluated palmitate’s long-term effects on SC-islets ( Aizenshtadt et al, 2024 ).…”

“…Furthermore, to accurately reflect the physiology of human islets, it is crucial to meticulously compare the utilization and responses of SC-islets to various nutrients with those of human primary islets ( Beydag-Tasöz et al, 2023 ; Jensen and Little, 2023 ). For example, we have coupled SC-islets and SC-liver organoids in a recirculating organ-on-chip (rOoC) platform and generated a metabolic crosstalk model between islets and liver ( Aizenshtadt et al, 2024 ). To provide insights before SC-islets spread into downstream utilization for drug testing and development, this study developed a merged protocol based on recently developed SC-islets differentiation protocols ( Hogrebe et al, 2020 ; 2021 ; Mahaddalkar et al, 2020 ).…”

A metabolic-dysfunction associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system

“…Therefore, it is necessary to implement more complex in vitro systems to study human physiology and pathophysiology, as well as disease progression that allow for the study of organ crosstalk and interaction. The development of human liver [37][38][39][40][41][42][43] pancreatic islets [44][45][46][47][48] , and coupled [49][50][51][52] biomimetic microphysiology systems (MPS) that can reflect the genomic, as well as environment and lifestyle heterogeneity offer an important opportunity to recapitulate the heterogeneity of disease.…”

Presentation1.pdf

“…Furthermore, to accurately reflect the physiology of human islets, it is crucial to meticulously compare the utilization and responses of SC-islets to various nutrients with those of human primary islets (Beydag-Tasöz et al, 2023;Jensen and Little, 2023). For example, we have coupled SC-islets and SC-liver organoids in a recirculating organ-on-chip (rOoC) platform and generated a metabolic crosstalk model between islets and liver (Aizenshtadt et al, 2024). To provide insights before SC-islets spread into downstream utilization for drug testing and development, this study developed a merged protocol based on recently developed SC-islets differentiation protocols (Hogrebe et al, 2020;Mahaddalkar et al, 2020).…”