Signaling pathways controlling pluripotency and early cell fate decisions of human induced pluripotent stem cells

Stem Cells. 2009 Nov;27(11):2655-66. doi: 10.1002/stem.199.


Human pluripotent stem cells from embryonic origins and those generated from reprogrammed somatic cells share many characteristics, including indefinite proliferation and a sustained capacity to differentiate into a wide variety of cell types. However, it remains to be demonstrated whether both cell types rely on similar mechanisms to maintain their pluripotent status and to control their differentiation. Any differences in such mechanisms would suggest that reprogramming of fibroblasts to generate induced pluripotent stem cells (iPSCs) results in novel states of pluripotency. In that event, current methods for expanding and differentiating human embryonic stem cells (ESCs) might not be directly applicable to human iPSCs. However, we show here that human iPSCs rely on activin/nodal signaling to control Nanog expression and thereby maintain pluripotency, thus revealing their mechanistic similarity to human ESCs. We also show that growth factors necessary and sufficient for achieving specification of human ESCs into extraembryonic tissues, neuroectoderm, and mesendoderm also drive differentiation of human iPSCs into the same tissues. Importantly, these experiments were performed in fully chemically defined medium devoid of factors that could obscure analysis of developmental mechanisms or render the resulting tissues incompatible with future clinical applications. Together these data reveal that human iPSCs rely on mechanisms similar to human ESCs to maintain their pluripotency and to control their differentiation, showing that these pluripotent cell types are functionally equivalent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors / antagonists & inhibitors
  • Activins / pharmacology
  • Adult
  • Animals
  • Benzamides / pharmacology
  • Bone Morphogenetic Protein 4 / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Culture Media
  • Dioxoles / pharmacology
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Female
  • Fibroblast Growth Factor 2 / pharmacology
  • Fibroblasts / cytology
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / physiology
  • Male
  • Mice
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / physiology
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / physiology
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*


  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Bone Morphogenetic Protein 4
  • Culture Media
  • Dioxoles
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Octamer Transcription Factor-3
  • Proto-Oncogene Proteins c-myc
  • SOXB1 Transcription Factors
  • Fibroblast Growth Factor 2
  • Activins
  • Activin Receptors