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HAND1 controls the lineage divergence between amnion and trophoblast from human pluripotent stem cells

ABSTRACT: Trophoblasts and amnion, as extra-embryonic lineages, can be differentiated from human pluripotent stem cells (PSCs) under defined culture conditions, but the regulatory mechanisms that coordinate the cell fate decisions between these lineages during PSC differentiation remain poorly defined. In this study, leveraging CRISPR/Cas9-mediated targeted screening and lineage reporter pluripotent stem cells (PSCs), we identified the transcription factor HAND1 as a critical determinant governing the divergence of trophoblast and amnion lineages in PSCs. Genetic ablation of HAND1 effectively suppressed the amnion differentiation capacity of EPSCs while enhancing their trophoblast differentiation potential. Conversely, ectopic overexpression of HAND1 have adverse effects. Notably, forced expression of HAND1 activated amnionic transcription program in human trophoblast stem cells (TSCs), demonstrating its lineage-reprogramming capability. Mechanistic analyses revealed that HAND1 cooperates with Wnt signaling pathway co-factors TCF/b-catenin to form a transcriptional complex that antagonistically regulates trophoblast- and amnion-associated gene networks. Collectively, our findings establish HAND1 as a pivotal regulator that orchestrates the fate choice between amnionic and trophoblast lineages during human PSC differentiation, providing insights into the molecular logic of extra-embryonic lineage specification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299501 | GEO | 2026/03/02

REPOSITORIES: GEO

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Project description:An increasing number of studies suggests that embryonic development is a highly plastic process and that lineage specification can proceed via alternative routes not encompassed in canonically defined germ layers. Despite these recent revisions to fate maps, the differentiation of pluripotent stem cells (PSCs) to specific lineages tends to continue to focus on defined germ layer differentiation. Thus although recent studies suggest that the visceral organs originate from both embryonic and extra-embryonic lineages, PSC differentiation has focused on generating definitive and gut endoderm solely via an embryonic trajectory. To better resolve the lineage trajectories during development and during corresponding in vitro differentiation, we used MARS-seq to generate a single-cell RNA-seq datasets from mouse embryos expressing a Foxa2Venus reporter and in vitro embryonic stem cell (ESC) differentiation towards definitive endoderm. We coupled this data to a new simplified computational approach to compare cell types, both within our own transcriptomes and across different datasets. Based on this analysis, we captured the central intermediate in the transition between extra-embryonic and embryonic endoderm. When we assessed in vitro ESC differentiation in a number of different endoderm protocols, we found no evidence for this transient intermediate population during differentiation, only traditional embryo-like populations. We then directly tested the capacity of extra-embryonic endoderm to generate organ specific cell types, exploiting our previously defined cell culture system for naïve extra-embryonic endoderm (nEnd). We found that nEnd exhibited gene expression states that reflects early extra-embryonic identity and could be further differentiated to embryonic gut organoids. Taken together, this suggests self-renewing extra-embryonic nEnd represents a source of definitive organ cell types and suggests that in vitro differentiation should take full advantage of the recent observations about developmental plasticity.

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HAND1 controls the lineage divergence between amnion and trophoblast from human pluripotent stem cells

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