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Cellular and Molecular Bioengineering

Cellular and Molecular Bioengineering - Poster Session E

Poster V6 - Metabolic dysfunction-associated steatohepatitis modeling using human liver organoids in liver-mimicking hydrogel

Saturday, October 26, 2024

10:00 AM – 11:00 AM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

JB

Jungho Bae

graduate student
Yonsei university
Seodaemun-gu, Seoul, United States

Co-Author(s)

SK

Su Kyeom Kim

Graduate student
Yonsei University, United States
ML

Mi Jeong Lee, MS

Graduate student
Yonsei University, United States

Primary Investigator(s)

SC

Seung-Woo Cho

Professor
Yonsei University, United States

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a leading cause of liver cirrhosis and liver cancer globally. Despite this growing health concern, there exists only one FDA-approved drug specifically designed to treat MASH. To better understand disease pathology and screen potential therapeutic candidates, developing an in vitro human steatohepatitis organoid model is essential. However, conventional fatty liver organoid models have several limitations, including the absence of non-parenchymal cells and the lack of a liver-specific extracellular matrix hydrogel, hindering the screening of potential drug candidates. Herein, we established stem cell-derived steatohepatitis organoid models through co-culture of liver-specific non-parenchymal cells in liver-mimicking (LM) hydrogel. Additionally, we evaluated the efficacy of drugs currently being used as clinical candidates for MASH in our organoid model. Our study demonstrates the development of a human liver microenvironment-integrated steatohepatitis organoid model using LM hydrogels and non-parenchymal cell co-culture, enabling more advanced disease modeling and candidate drug screening.

Materials and

Methods: Liver organoids were generated with human induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs). To fabricate human iPSC-derived liver organoids, several types of non-parenchymal cells constituting liver microenvironments were mixed with human iPSC-derived hepatic endodermal cells in LM hydrogel.
To generate human ASC-derived liver organoids, adult liver ductal cells were isolated from liver tissue and encapsulated in LM hydrogel with optimized cell density. Several non-parenchymal cells were co-cultured with liver organoids in liver organoid culture medium, followed by additional hepatic differentiation culture.
For steatohepatitis induction, all the human liver organoids in this study were treated with free fatty acid in each culture medium.

Results, Conclusions, and Discussions: In this study, we generated ASC- and iPSC-derived liver organoids co-cultured with liver-specific non-parenchymal cells using LM hydrogel to recapitulate human liver microenvironments. Our results demonstrated that non-parenchymal cell-containing liver organoids exhibited upregulated gene expressions of hepatocyte-related markers and enhanced hepatic functions. Our MASH organoid models showed increased lipid droplet deposition and upregulation of disease phenotypic markers. Additionally, we confirmed the efficacy of existing MASH drug candidates using our MASH models. In conclusion, our liver specific microenvironment-integrated MASH organoid models closely resemble human MASH phenotypes, which can be applied to more accurate disease modeling and high-reliability drug evaluation platforms.

Acknowledgements (Optional): This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. 2022M3A9B6082675). The work was supported in part by Brain Korea 21(BK21) FOUR program.