Language
English
Publication Date
9-22-2026
Journal
Cell Reports
DOI
10.1016/j.celrep.2026.117953
PMID
42726640
PMCID
PMC13650770
PubMedCentral® Posted Date
10-10-2026
PubMedCentral® Full Text Version
Author MSS
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.
Keywords
Animals, Signal Transduction, Humans, eIF-2 Kinase, Receptor, Notch3, Regeneration, Adaptor Proteins, Signal Transducing, Mice, Calcium-Binding Proteins, Hematopoietic Stem Cells, Intracellular Signaling Peptides and Proteins, Mice, Inbred C57BL, Stem Cell Niche
Published Open-Access
yes
Recommended Citation
Zou, Bingqing; Chen, Qiuyun; Zheng, Junjun; et al., "Endothelial Perk Restricts Lymphoid Regeneration by Reducing DLL4-NOTCH3 Signaling at the Pre-B Niche" (2026). Faculty, Staff and Students Publications. 8580.
https://digitalcommons.library.tmc.edu/baylor_docs/8580
Graphical Abstract