Transposable element activity captures human pluripotent cell states

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Genomics

Background:

• Human pluripotent stem cells (hPSCs) model early human development but their distinct states are poorly understood.
• Molecular regulators of pluripotency and differentiation remain incompletely characterized.
• Transposable elements (TEs) are increasingly recognized for their roles in genome regulation and cell state dynamics.

Purpose of the Study:

• To develop a novel reporter system for real-time monitoring of hPSC states.
• To identify molecular determinants governing transitions between naïve and primed pluripotency.
• To uncover novel cell populations and regulatory mechanisms within hPSCs.

Main Methods:

• Engineering hPSCs with dual fluorescent reporters for specific TEs (LTR5_Hs, MER51B).
• Real-time tracking and isolation of hPSCs undergoing pluripotency state transitions.
• Transcriptomic analysis to characterize cell populations and identify regulatory factors.

Main Results:

• TEs serve as sensitive indicators of distinct hPSC states and pluripotency dynamics.
• The dual reporter system accurately monitors transitions from naïve to primed pluripotency and differentiation.
• A rare, metastable primed hPSC population with preimplantation embryo development signatures and DNA damage response was identified.
• NSD1 and FUS were identified as crucial safeguards of primed pluripotency.

Conclusions:

• Transposable elements provide a powerful tool for dissecting hPSC states and developmental trajectories.
• The novel reporter system offers a more accurate readout of pluripotency compared to conventional methods.
• Understanding TEs and associated factors like NSD1 and FUS is critical for controlling hPSC fate and applications in regenerative medicine and developmental studies.