Epigenetic resetting of human pluripotency

Area of Science:

• Stem cell biology
• Developmental biology
• Epigenetics

Background:

• Human pluripotent stem cells (PSCs) are crucial for developmental studies.
• Converting PSCs to a naive state is challenging but essential for understanding early human development.
• Existing methods for PSC reprogramming have limitations.

Purpose of the Study:

• To establish a robust and efficient method for converting human PSCs to a naive developmental state.
• To characterize the epigenetic and transcriptional features of the reset cells.
• To assess the developmental potential of the reset PSCs.

Main Methods:

• Transient inhibition of histone deacetylase in human PSCs.
• WNT pathway inhibition to stabilize the resetting process.
• Transcriptomic, epigenetic, and differentiation assays.

Main Results:

• A novel protocol effectively resets multiple PSC lines to a naive state without karyotype changes.
• Reset cells exhibit feeder-free expansion with a 24-hour doubling time.
• Transcriptome analysis reveals similarities to human inner cell mass (ICM) cells, including primate-specific transposable element activation and global DNA hypomethylation.
• Reset cells can re-differentiate into tri-lineage tissues and germ cells.
• Reactivation of the silenced X chromosome in female reset cells, with subsequent XIST-mediated silencing upon re-priming.

Conclusions:

• Transient histone deacetylase inhibition provides a facile and robust method for generating naive human PSCs.
• The reset cells possess characteristics of early embryonic cells and retain developmental plasticity.
• This method will accelerate research into naive PSCs and early human development.