Multi‐omics analysis of hiPSCs‐derived HLCs matured on‐chip revealed patterns typical of liver regeneration

Abstract Maturation of human‐induced pluripotent stem cells (hiPSCs)‐derived hepatocytes‐like cells (HLCs) toward a complete hepatocyte phenotype remains a challenge as primitiveness patterns are still commonly observed. In this study, we propose a modified differentiation protocol for those cells which includes a prematuration in Petri dishes and a maturation in microfluidic biochip. For the first time, a large range of biomolecular families has been extracted from the same sample to combine transcriptomic, proteomic, and metabolomic analysis. After integration, these datasets revealed specific molecular patterns and highlighted the hepatic regeneration profile in biochips. Overall, biochips exhibited processes of cell proliferation and inflammation (via TGFB1) coupled with anti‐fibrotic signaling (via angiotensin 1‐7, ATR‐2, and MASR). Moreover, cultures in this condition displayed physiological lipid‐carbohydrate homeostasis (notably via PPAR, cholesterol metabolism, and bile synthesis) coupled with cell respiration through advanced oxidative phosphorylation (through the overexpression of proteins from the third and fourth complex). The results presented provide an original overview of the complex mechanisms involved in liver regeneration using an advanced in vitro organ‐on‐chip technology.