Hypoxia-activated scleraxis a mediates epicardial progenitor differentiation into a unique cardiac perivascular cell type.

Bj&#xf6;rn Perder; Yu Xia; Jun Yao; Ignace Van der Wee; Miaoyan Qiu; Alvin Gea Chen Yao; Muhammad Naeem; Paul Zumbo; Avi Yakubov; Stephanie L Tsai; Kazu Kikuchi; Jenna L Galloway; Doron Betel; Todd Evans; Michael R M Harrison; Jingli Cao

doi:10.1038/s41467-026-77008-y

PubMed · 42754619

Hypoxia-activated scleraxis a mediates epicardial progenitor differentiation into a unique cardiac perivascular cell type.

Björn Perder·Yu Xia·Jun Yao·Ignace Van der Wee·Miaoyan Qiu·Alvin Gea Chen Yao·Muhammad Naeem·Paul Zumbo·Avi Yakubov·Stephanie L Tsai·Kazu Kikuchi·Jenna L Galloway·Doron Betel·Todd Evans·Michael R M Harrison·Jingli Cao

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Abstract

The epicardium provides progenitor cells and paracrine signals essential for heart development and regeneration, yet the mechanisms regulating epicardial cell fate remain poorly understood. Here, we identify the transcription factor Scleraxis a (scxa) as a key regulator of epicardial progenitor differentiation in zebrafish. Single-cell transcriptomics, genetic lineage tracing, and cardiac injury models reveal transient scxa expression in activated epicardial progenitor cells (aEPCs) during developmental coronary angiogenesis and heart regeneration. scxa+ epicardial cells predominantly differentiate into a previously uncharacterized col18a1a+ perivascular population, termed epicardial-derived perivascular mesenchymal cells (Epi-PMCs), which is distinct from pericytes, vascular smooth muscle cells, and mammalian adventitial fibroblasts. Epi-PMCs closely associate with coronary vessels and may contribute to vascular stabilization and remodeling, potentially through collagen XVIII. Loss of scxa increases coronary vessel density. Hypoxia and Hif signaling induce scxa expression, identifying a hypoxia-responsive mechanism that promotes epicardial differentiation toward a vascular-supportive fate during heart development and regeneration.

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Animals Zebrafish Cell Differentiation Pericardium Basic Helix-Loop-Helix Proteins Coronary Vessels Zebrafish Proteins Stem Cells Hypoxia Regeneration Neovascularization, Physiologic Mesenchymal Stem Cells Journal Article

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Björn Perder, Yu Xia, Jun Yao, Ignace Van der Wee, Miaoyan Qiu, Alvin Gea Chen Yao, Muhammad Naeem, Paul Zumbo, Avi Yakubov, Stephanie L Tsai, Kazu Kikuchi, Jenna L Galloway, Doron Betel, Todd Evans, Michael R M Harrison, Jingli Cao. 2026-08-20. Hypoxia-activated scleraxis a mediates epicardial progenitor differentiation into a unique cardiac perivascular cell type.. https://doi.org/10.1038/s41467-026-77008-y

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