Document Type

Article

Publication Date

4-22-2025

Keywords

JGM, SS1, Humans, Mesoderm, Induced Pluripotent Stem Cells, Animals, Mice, Terminal Repeat Sequences, Trophoblasts, Cell Differentiation, Endogenous Retroviruses, Protein Binding, Cell Line, Basic Helix-Loop-Helix Transcription Factors

JAX Source

Cell Rep. 2025;44(4):115568.

ISSN

2211-1247

PMID

40220298

DOI

https://doi.org/10.1016/j.celrep.2025.115568

Grant

his study was funded by the National Institutes of Health grant 1UM1HG012651 (W.C.S. and P.R.), National Institutes of Health grant 1U54AG075941 (P.R.), National Institutes of Health grant 5P30CA034196 (P.R.), and Fulbright- Thailand Research Fund Junior Research Scholarship PHD/0123/2556 (P.P.)

Abstract

The specification of extra-embryonic mesenchyme (ExMC) is a prime example of developmental divergence between mouse and human. Derived from definitive mesoderm during mouse gastrulation, the human ExMC first appears at peri-implantation prior to gastrulation and therefore its human cellular origin, still unknown, must differ. In a human pluripotent stem cell model, we report that ExMC shares progenitor cells with trophoblast, suggesting a trophectoderm origin. This ability to form ExMC appears to extend to human trophoblast stem cell lines. We define HAND1 as an essential regulator of ExMC specification, with null cells remaining in the trophoblast lineage. Bound by HAND1, ape-specific, endogenous retrovirus-derived LTR2B contributes to unique features of ExMC. Additionally, ExMC supports the maintenance of pluripotent stem cells, possibly reflecting a role in maintaining epiblast pluripotency through peri-implantation development. Our data emphasize the nascent evolutionary innovation in human early development and provide a cellular system to study this.

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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