Fig. 4

Mature hepatocyte differentiation from human pluripotent stem cells (hPSC). a Human pluripotent stem cell (hPSC)-derivation. hPSC either can be human embryonic stem cells (hESC) or human induced pluripotent stem cells (hiPSC). hESC are derived from the fertilized human embryo at the blastocyst/epiblast stage of development. hiPSC are derived from any cells of the patient, typically fibroblasts. Typically, four factors are activated within the fibroblasts to engineer iPSC, which are patient-specific. Cells are maintained in colonies with specialized serum-free medium and cultivated on basement membrane-resembling matrix. b Gastrulation. hPSC undergo similar signaling to what occurs during early development of the organism into germ layers, such as ectoderm, endoderm, and mesoderm. Activin and/or Wnt activate key pathways that induce primitive streak mesendoderm and endoderm from hPSC. The transcription factors and cell surface markers activated are as shown. c Embryonic liver development. hPSC-endoderm can form hepatic endoderm (HE) in the presence of growth factors (FGF2 from cardiac mesoderm (CM), BMP4 from septum transversum mesenchyme (STM), and cell-cell contacts with endothelial cells. These then activate HE specific markers. The HE cells delaminate out of the epithelium into the STM during this stage and form hepatoblasts in the presence of HGF. The cells from cords of hepatoblasts (markers as shown). The STM is obliterated. Markers are as shown. d Fetal, neonatal, and adult liver development. hPSC-hepatoblasts can be matured in the presence of maturating agents like Dexamethasone, Oncostatin, and Insulin, Selenium, and Transferrin (ITS). The result is fetal, neonatal, immature, and eventually, mature hepatocyte cells. These mature cells can potentially be used in a wide range of hepatic devices, basic studies, and cell therapy protocols