Metabolomic profiling during the differentiation of human induced pluripotent stem cells into hepatocyte-like cells

International audienceHuman induced pluripotent stem cells (hiPSC) potentially present an invaluable source of cells for regenerative medicine, disease modeling and drug discovery. However, hiPSC differentiation into fully functional hepatocytes remains a major challenge. Despite the importance of information carried by metabolomes, the exploitation of metabolomics for characterizing and understanding of hiPSC differentiation remains largely unexplored. Here, to increase the knowledge on hiPSC maturation into mature hepatocytes, we investigated their metabolomics profiles during a sequential step-by-step differentiation: definitive endoderm (step 1), specification into hepatocytes (step 2), progenitor hepatocytes (step 3) and mature hepatocyte-like cells (step 4). Metabolomics biomarkers illustrated a switch from glycolysis-based respiration in step 1 to an oxidative phosphorylation in step 4. The step 1 was characterised by fatty acids beta oxidation, sorbitol metabolism and pentose phosphate pathway, glutamine and glucose metabolisms as potential various energy source. Complex lipid metabolism switch was monitored via the reduction of lipid production from steps 1 to 4, whereas high glycerol production occurred mainly step 4. The nitrogen cycle, via the urea production also was typical mechanism revealed in step 4. Our analysis may contribute to a better understanding of differentiation and suggest novel targets to improve iPSC maturation into functional hepatocytes