Establishment of a physiologically-relevant liver model for disease screening

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22491
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0403:Biomedical engineering and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Danoy Mathieu 東京大学, 大学院工学系研究科(工学部), 助教 (90882621)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: hiPSCs / HSCs / Liver / Disease / LSECs / Hepatocytes / Inflammation / Immune

Outline of Final Research Achievements

Ethical issues and species specificity have motivated the development of in vitro models of the liver for drug screening applications. Modeling of the liver is especially challenging due to its complexity, being composed of hierarchically organized hepatocytes, LSECs, and HSCs. Here, the focus was set on the development of the latter which are known to be involved in inflammatory regulation but spontaneously activate when cultured in vitro, causing issues in the modeling of physiology. To solve the issue, optimization of the microenvironment of HSCs in term of stiffness and composition was done via different ECM. By doing so, optimized conditions in which quiescence could be preserved were found and controlled activation, via inflammatory cytokines was also confirmed. Protocols for the differentiation of those cells were also optimized in terms of reproducibility. Coculture of the previously cited cell types was also performed in microfluidic biochips and are currently further studied.

Free Research Field

Bioengineering

Academic Significance and Societal Importance of the Research Achievements

Physiologically-relevant models are highly sought for in notably drug screening applications but spontaneous activation of HSCs in vitro forces models towards pathological situation. In this work, we have focused on optimizing the culture of HSCs to regulate inflammatory reactions within the model.