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Updated: Jun 25, 2026
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Chemical Reversion of Conventional Human Pluripotent Stem Cells to a Naïve-like State with Improved Multilineage Differentiation Potency
Published on: June 10, 2018
Klf4 reverts developmentally programmed restriction of ground state pluripotency
Ge Guo1, Jian Yang, Jennifer Nichols
1Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK.
Development (Cambridge, England)
|February 20, 2009
Summary
Reprogramming mouse epithelialised epiblast stem cells (EpiSCs) back into embryonic stem cells (ES cells) requires Klf4 and specific culture conditions. This process regenerates the naïve pluripotency of ES cells, offering insights into developmental reprogramming.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Epigenetics
Background:
- Embryonic stem (ES) cells from early epiblast are pluripotent and form all fetal lineages.
- Epithelialised epiblast stem cells (EpiSCs) from post-implantation epiblast express pluripotency genes but cannot colonize embryos.
- ES cells convert to EpiSCs, but not vice versa, indicating distinct states.
Purpose of the Study:
- To investigate the interconversion between ES cells and EpiSCs.
- To determine if EpiSCs can be reprogrammed back to a pluripotent ES cell state.
- To identify factors and conditions necessary for reprogramming EpiSCs.
Main Methods:
- Utilized PiggyBac transposition to introduce Klf4 into EpiSCs.
- Cultured reprogrammed cells under both EpiSC and ground state ES cell conditions.
- Analyzed gene expression, X chromosome inactivation, and chimaeric contribution of reprogrammed cells.
Main Results:
- Klf4 expression in EpiSCs under ES cell conditions induced undifferentiated colonies (Epi-iPS cells).
- Epi-iPS cells expressed ES cell markers, downregulated lineage specification markers, and erased X chromosome silencing.
- Epi-iPS cells generated high-contribution chimaeras with germline transmission, demonstrating stable reprogramming.
Conclusions:
- Klf4, in conjunction with suppressed extrinsic growth factor stimuli, can fully reprogram EpiSCs to the naïve ES cell ground state.
- EpiSCs are developmentally, epigenetically, and functionally distinct from ES cells.
- EpiSCs serve as a valuable model for screening unknown reprogramming factors due to the minimal requirement of a single transgene for reprogramming.
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