ETV2-ECSCR-mTOR pathways regulate reprogramming to the endothelial lineage

Feb 7, 2026Stem cells (Dayton, Ohio)

ETV2, ECSCR, and mTOR pathways control cell change into blood vessel lining cells

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Abstract

Ecscr is identified as a direct transcriptional target of ETV2 that plays a key role in endothelial cell reprogramming.

Single-cell RNA sequencing showed upregulation of Ecscr in cell populations induced by ETV2 during differentiation.
ETV2 was confirmed to bind to the Ecscr gene through various assays, including ATAC-seq and ChIP-seq.
Ecscr knockdown significantly enhanced the rate of cell reprogramming, indicating its role in modulating ETV2 activity.
The knockdown of Ecscr resulted in the upregulation of Rptor, a critical component of the mTORC1 complex.
Inhibition of mTORC1 signaling with rapamycin partially reversed the effects of Ecscr knockdown, suggesting mTORC1 mediates ETV2's influence.

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ETV2 is a pioneer factor that regulates cell fate decisions and direct reprogramming of the endothelial lineage. While ETV2 drives the cell fate conversion through epigenetic remodeling, its downstream targets also contribute to ETV2-mediated cell fate conversion. In this study, we defined Ecscr as a direct transcriptional target of ETV2 and a key regulator of ETV2-mediated cell reprogramming. Single-cell RNA sequencing analyses of ETV2-overexpressing embryoid body differentiation and embryonic fibroblast reprogramming revealed upregulation of Ecscr in ETV2-induced cell populations. ATAC-seq, ChIP-seq, gel shift, and transcriptional assays confirmed ETV2 binding to the Ecscr gene. In vivo analyses using 3.9 kb-Etv2-EYFP reporter transgenic mice and Etv2 null mice, in combination with single-cell RNA-seq of developing mouse embryos, further validated Ecscr as an ETV2 downstream target. Functionally, the knockdown of Ecscr significantly enhanced reprogramming rate, suggesting that Ecscr functions in a feedback mechanism to decrease the ETV2-mediated cell fate conversion. Mechanistically, Ecscr knockdown led to upregulation of Rptor, a core component of mTORC1 complex. The inhibition of mTORC1 signaling with rapamycin partially reversed the effect, supporting the notion that mTORC1 functions as a downstream mediator. Our findings uncover a novel ETV2 downstream target ECSCR that modulates ETV2-driven reprogramming through mTORC1 regulation, offering a target to improve endothelial reprogramming for regenerative applications.

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ETV2-ECSCR-mTOR pathways regulate reprogramming to the endothelial lineage

Abstract

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