High resolution multi-scale profiling of embryonic germ cell-like cell derivation reveals pluripotent state transitions in humans
Year: 2025
Type: article
Abstract: Primordial germ cells (PGCs) are the embryonic precursors of the gametes. In mice and rats, PGCs can readily acquire pluripotency in vitro by forming embryonic germ cells (EGCs). To date, a comparable in vitro system has not been established in humans, despite the fact that human PGCs (hPGCs) readily undergo pluripotent conversion in the context of germ cell tumorigenesis. Here we report that hPGC-like cells (hPGCLCs) undergo conversion to human embryonic germ-like cells (hEGCLCs) upon exposure to the same inductive signals previously used to derive mouse EGCs. This defined, feeder-free culture system allows efficient derivation of human EGCLCs which can be expanded and maintained in standard human pluripotent stem cell medium. hEGCLCs are transcriptionally similar to human pluripotent stem cells (hPSCs) and can differentiate into all three germ layers, as well as giving rise to PGCLCs once more - demonstrating the interconvertibility of pluripotent states. This is also evident at the epigenetic level, as the initial DNA demethylation that occurs in hPGCLCs is largely reversed in hEGCLCs, restoring DNA methylation to the level observed in hPSCs. This new in vitro model captures the transition from the pluripotent stem cell state to a germ cell identity and back again, and therefore represents a highly tractable system to study pluripotent and epigenetic transitions, including those which occur during human germ cell tumorigenesis. Graphical abstract In brief We report the first fully defined system to efficiently convert hPGCLCs to a pluripotent stem cell (PSC) state. We tracked pluripotent state transitions by multi-omic analysis and provided a high-resolution map of the transcriptional and epigenomic transitions upon entry to and exit from the human germline. Highlights Efficient derivation of hEGCLC in fully defined feeder-free conditions Single-cell transcriptomic profiling of transitions from the hPSC state to hPGCLCs and back. Longitudinal DNA methylation profiling highlights the overall reversibility of epigenetic states Multi-omic gene regulatory network analysis identifies key regulators of pluripotent transitions
Source: Stem Cell Reports
Authors: Sarah Stucchi, Lessly P. Sepulveda-Rincon, Camille Dion, Gaja Matassa, Alessia Valenti, Cristina Cheroni, Alessandro Vitriolo, Filippo Prazzoli, George Young, Marco Tullio Rigoli, Riccardo Nagni, Martina Ciprietti, Benedetta Muda, Zoe Heckhausen, Petra Hajkova, Nicolò Caporale, Giuseppe Testa, Harry G. Leitch
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Funders: National Institute on Handicapped Research, National Institute for Health and Care Research, European Commission, Horizon 2020 Framework Programme, Medical Research Council, Great Ormond Street Institute of Child Health, NIHR Imperial Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre
Awards: G1956448824, Building REsilience against MEntal illness during ENDocrine-sensitive life stages, G3774665350, Risk and Resilience in Developmental Diversity and Mental Health, Novel Testing Strategies for Endocrine Disruptors in the Context of Developmental NeuroToxicity, The pandemic within: tackling brain vulnerability in COVID19 at high resolution: NEUROCOV
OpenAlex ID: W4417485635