Current Status and Challenges of Human Induced Pluripotent Stem Cell-Derived Liver Models in Drug Discovery

Abstract

The pharmaceutical industry is in high need of efficient and relevant in vitro liver models, which can be incorporated in their drug discovery pipelines to identify potential drugs and their toxicity profiles. Current liver models often rely on cancer cell lines or primary cells, which both have major limitations. However, the development of human induced pluripotent stem cells (hiPSCs) has created a new opportunity for liver disease modeling, drug discovery and liver toxicity research. hiPSCs can be differentiated to any cell of interest, which makes them good candidates for disease modeling and drug discovery. Moreover, hiPSCs, unlike primary cells, can be easily genome-edited, allowing the creation of reporter lines or isogenic controls for patient-derived hiPSCs. Unfortunately, even though liver progeny from hiPSCs has characteristics similar to their in vivo counterparts, the differentiation of iPSCs to fully mature progeny remains highly challenging and is a major obstacle for the full exploitation of these models by pharmaceutical industries. In this review, we discuss current liver-cell differentiation protocols and in vitro iPSC-based liver models that could be used for disease modeling and drug discovery. Furthermore, we will discuss the challenges that still need to be overcome to allow for the successful implementation of these models into pharmaceutical drug discovery platforms.

Toward 3D‐Bioprinted Models of the Liver to Boost Drug Development

“…[ 66,67 ] Among them, hepatocytes derived from induced pluripotency stem cells (iPSC) and HepaRG (which are bipotent cells able to differentiate into hepatocytes or hepatic stellate cells) are extremely promising for this kind of application, due to their high fidelity in reproducing the physiological metabolic activity. [ 68–70 ]…”

Liver organ-on-chip models for toxicity studies and risk assessment

“…Moreover, the cells obtained are only partially mature and the protocols used still need to be improved by optimizing culture medium (small molecules and growth factors concentrations), supports of culture (3D, ECM and dynamic microfluidic cultures) and coculture of different liver cell types. 144 3.3 Different liver OoC approaches 3.3.1 2D monolayer culture. The most common approach when developing microfluidic systems for the monolayer culture of cells is based on lithography patterned substrates.…”

“…Moreover, the cells obtained are only partially mature and the protocols used still need to be improved by optimizing culture medium (small molecules and growth factors concentrations), supports of culture (3D, ECM and dynamic microfluidic cultures) and coculture of different liver cell types. 144…”

Application of hiPSC as a Drug Tester Via Mimicking a Personalized Mini Heart

“…Then large animals are considered as the further step before clinical transition to measure specific cardiac electrophysiology. This approach can lead to the simulation of potential drug reactions in different organs throughout the body, although numerous failures have reminded researchers that interspecies differences may represent a barrier to fully transfer experimental test results to clinic practice ( Pavez-Giani and Cyganek, 2021 ; Bourque et al, 2022 ; Tricot et al, 2022 ). Then the human based clinical trial is critical to fully validate a newly invented drugs.…”