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

Area of Science:

• Hematology
• Immunology
• Cell Biology

Background:

• Delayed immune recovery post-hematopoietic stem cell (HSC) transplantation leads to poor outcomes.
• Limited strategies exist to enhance lymphocyte regeneration.
• Endothelial ER stress in the bone marrow (BM) microenvironment impacts hematopoietic regeneration.

Purpose of the Study:

• Investigate the role of ER stress in hematopoietic regeneration within the BM microenvironment.
• Elucidate the mechanism of ER stress-mediated regulation of immune cell recovery.
• Identify therapeutic targets to improve immune reconstitution after transplantation.

Main Methods:

• Studied ER stress (PERK activation) in BM endothelium of leukemia patients and irradiated mice.
• Utilized genetic ablation of endothelial Perk in mice.
• Performed single-cell analysis to examine cell-cell signaling pathways.
• Assessed HSC and B progenitor regeneration, DLL4 and NOTCH3 expression, and IL7 cytokine production.

Main Results:

• PERK activation is prominent in BM endothelium following irradiation.
• Ablating endothelial Perk increased DLL4 expression, promoting HSC and B progenitor regeneration.
• Endothelial DLL4 activates NOTCH3 on mesenchymal stroma cells, coordinating lymphoid commitment.
• The PERK-DLL4-NOTCH3 axis regulates IL7 production and lymphoid progenitor expansion.

Conclusions:

• Uncovered a novel ER stress-controlled vascular-stroma signaling pathway in regenerative hematopoiesis.
• PERK blockade enhances DLL4-NOTCH3 signaling and IL7 production, promoting immune recovery.
• PERK inhibition represents a promising therapeutic strategy for improving immune reconstitution after myeloablative transplantation.