Targeting Endothelial PERK Accelerates Lymphoid Regeneration by Enhancing DLL4-NOTCH3 Signaling at the Pre-B Niche

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome, yet strategies to enhance lymphocyte regeneration are limited. We studied the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We revealed that PERK activation is a prominent feature of BM endothelium in leukemia patients and is a hallmark response in mouse BM following ionizing irradiation. Ablating endothelial Perk boosted Notch ligand DLL4 expression and promoted DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis shows that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment and niche cytokine production. NOTCH3 is critical for the upregulation of IL7 following irradiation and for supporting the expansion of lymphoid progenitors in mesenchymal sphere cultures. These findings not only unveil a previously unrecognized ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising therapeutic strategy to improve immune recovery after myeloablative transplantation.