A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells

Cell Rep. 2018 Feb 20;22(8):2190-2205. doi: 10.1016/j.celrep.2018.01.087.


How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-β, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3+HNF4A+ human liver bud progenitors and 81.5% ± 3.2% FAH+ hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah-/-Rag2-/-Il2rg-/- mouse model of liver failure.

Keywords: efficient differentiation; human liver development; pluripotent stem cells; progenitor; signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biliary Tract / cytology
  • Biomarkers / metabolism
  • Bone Morphogenetic Proteins / pharmacology
  • Cell Differentiation* / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Endoderm / cytology
  • Fibroblast Growth Factors / pharmacology
  • Gastrointestinal Tract / cytology
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • High-Throughput Screening Assays
  • Humans
  • Liver / cytology*
  • Liver / injuries
  • Liver / pathology
  • Mice
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / drug effects
  • Signal Transduction
  • Tretinoin / pharmacology
  • Wnt Signaling Pathway / drug effects


  • Biomarkers
  • Bone Morphogenetic Proteins
  • Tretinoin
  • Fibroblast Growth Factors
  • Cyclic AMP-Dependent Protein Kinases