Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Authors

Bingqing Zou, Qiuyun Chen, Junjun Zheng, Yimin Ma, Jay Myers, Yinghui Shang, Mofei Huang, Paul Christensen, Stanley Adoro, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Sai Ravi Kiran Pingali, Wei Xin, Keith Syson Chan, Stephen Wong, Youli Zu, Hamed Jafar-Nejad, Lan Zhou

Published in

Cell reports. Volume 45. Issue 9. Pages 117953. Sep 10, 2026. Epub Sep 10, 2026.

Abstract

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

PMID:
42726640
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.

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