Reprogramming roadmap reveals route to human induced trophoblast stem cells.

Area of Science:

• Cell Biology
• Developmental Biology
• Genomics

Background:

• Human somatic cell reprogramming to induced pluripotent stem cells (iPSCs) mimics early embryonic development but lacks mechanistic understanding.
• This knowledge gap hinders optimization of reprogramming protocols and understanding of developmental processes.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying human somatic cell reprogramming into primed and naive pluripotent states.
• To identify key regulatory elements and transcription factors involved in these distinct reprogramming trajectories.
• To explore the potential for deriving novel stem cell types during reprogramming.

Main Methods:

• Single-cell transcriptomics to reconstruct molecular reprogramming trajectories.
• Genome-wide analyses of accessible chromatin to identify regulatory element changes.
• Integrated analysis of transcriptomic and epigenomic data.

Main Results:

• Reprogramming to primed and naive pluripotency follows distinct molecular pathways.
• Significant changes in chromatin accessibility at regulatory elements of pluripotency genes were observed.
• A trophectoderm-like cell state was identified and captured, leading to the derivation of induced trophoblast stem cells (iTSCs).
• Derived iTSCs exhibit molecular and functional similarity to naturally occurring trophoblast stem cells.

Conclusions:

• A high-resolution roadmap for transcription-factor-mediated reprogramming of human somatic cells was established.
• The trophectoderm lineage regulatory program plays a role in somatic cell reprogramming.
• Direct reprogramming of somatic cells into iTSCs is feasible, offering a new avenue for stem cell research and applications.