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Resetting transcription factor control circuitry toward ground-state pluripotency in human
Yasuhiro Takashima1, Ge Guo2, Remco Loos3
1Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
Cell
|September 13, 2014
Summary
Researchers successfully reprogrammed human stem cells to a ground state by expressing NANOG and KLF2. This rewiring enhances self-renewal and stability, mimicking mouse embryonic stem cells (ESC) for potential therapeutic applications.
Area of Science:
- Stem cell biology
- Epigenetics
- Molecular genetics
Background:
- Human pluripotent stem cells (hPSCs) differ from mouse ESCs due to distinct transcription factor networks.
- Achieving a stable, ground-state pluripotency in hPSCs is crucial for regenerative medicine.
Purpose of the Study:
- To engineer a functional ground-state pluripotency circuitry in human cells.
- To investigate the molecular mechanisms underlying ground-state pluripotency induction.
Main Methods:
- Transient expression of NANOG and KLF2 to initiate network rewiring.
- Inhibition of ERK and protein kinase C pathways to sustain the reset state.
- Analysis of self-renewal, differentiation potential, metabolism, DNA methylation, and transcriptome.
Main Results:
- Short-term NANOG and KLF2 expression successfully reset hPSCs to a ground state.
- Inhibition of specific signaling pathways maintained a transgene-independent, rewiring state.
- Reset cells exhibited enhanced self-renewal, stability, and metabolic profiles similar to ESCs.
- Global reduction in DNA methylation and transcriptome realignment were observed.
- Ground-state transcription factors (TFCP2L1, KLF4) were critical for maintaining the reset state.
Conclusions:
- It is feasible to install and propagate functional control circuitry for ground-state pluripotency in human cells.
- This approach offers a pathway to generate more robust and ESC-like pluripotent cells for research and therapy.
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