Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

Development. 2016 Dec 1;143(23):4368-4380. doi: 10.1242/dev.138982. Epub 2016 Sep 22.


The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i). LIF-3i-reverted hPSCs retained normal karyotypes and genomic imprints, and attained defining mouse ESC-like functional features, including high clonal self-renewal, independence from MEK/ERK signaling, dependence on JAK/STAT3 and BMP4 signaling, and naïve-specific transcriptional and epigenetic configurations. Tankyrase inhibition promoted a stable acquisition of a human preimplantation ICM-like ground state via modulation of WNT signaling, and was most efficacious in efficiently reprogrammed conventional hiPSCs. Importantly, naïve reversion of a broad repertoire of conventional hiPSCs reduced lineage-primed gene expression and significantly improved their multilineage differentiation capacities. Stable naïve hPSCs with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling.

Keywords: Differentiation; Ground state; Human embryonic stem cell; Induced pluripotent stem cell; Naïve pluripotency.

Publication types

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

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Differentiation / physiology*
  • Cell Self Renewal / physiology*
  • Cells, Cultured
  • Cellular Reprogramming / physiology
  • Embryonic Stem Cells / cytology*
  • Germ Layers / embryology
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Janus Kinases / metabolism
  • Leukemia Inhibitory Factor / metabolism
  • Mice
  • STAT3 Transcription Factor / metabolism
  • Tankyrases / antagonists & inhibitors*
  • Wnt Signaling Pathway / physiology*


  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • LIF protein, human
  • Leukemia Inhibitory Factor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tankyrases
  • Janus Kinases
  • Glycogen Synthase Kinase 3 beta