Graduate Student Yonsei University, Republic of Korea
Abstract: The prevalence of steatohepatitis is on the rise annually, with metabolic dysfunction-associated steatohepatitis (MASH) emerging as a significant contributor to global liver cirrhosis and cancer. Despite its growing impact on public health, there exists only one FDA-approved drug designed to treat MASH. To understand disease pathology and screen potential therapeutic candidates, the development of an in vitro human liver-mimetic steatohepatitis organoid model is crucial. Conventional fatty liver organoid models for therapeutic candidate screening are constrained by several limitations, such as the absence of non-parenchymal cells (NPCs), the absence of a liver-specific extracellular matrix (ECM), and insufficient understanding of mechanisms related to MASH progression. Herein, we established stem cell-derived advanced steatohepatitis organoid models through co-culture of endothelial cells, hepatic stellate cells, and Kupffer cells combined with liver-mimicking hydrogel. We also developed an organoid chamber chip for efficient fatty acid accumulation inside the organoid, and simultaneously, allows for on-chip drug screening. Compared to existing steatosis organoid models, which are typically cultured in Matrigel under static well-plate condition, our advanced steatohepatitis organoid model exhibited a phenotype closely resembling the characteristics observed in actual MASH patients. Our study highlights the development of the first human liver microenvironment-incorporated steatohepatitis organoid model for drug screening, contributing to the understanding of drug mechanisms related to the progression of MASH.
Funding Source: This research was supported by the ABC-based Regenerative BioTherapeutics (ABC project) grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Health & Welfare) (RS-2024-00432653) and by Brain Korea 21.
