Endothelial PERK Impairs Post-transplant Lymphoid Regeneration by Reducing DLL4-NOTCH3 Signaling at the Pre-B Niche

We evaluated how endothelial PERK-DLL4 axis regulates early HSC and B progenitor regeneration by using single-cell analysis of regenerating bone marrow cells collected from mice with endothelial-specific deletion of Perk (EP), Dll4 (ED), or combined (DKO). Through bone marrow transplantation and single cell analysis, we revealed that perturbation of PERK or DLL4 resulted in opposite changes in B and granulomonocytic progenitor recovery.

Further, PERK-DLL4 axis orchestrates the regenerative network by regulating endothelial DLL4 signaling to NOTCH3 on MSCs, lymphoid commitment of hematopoietic stem cells, IL7 expression in MSCs, and coordinated interferon response. These findings establish that ER stress regulates a regenerative pre-B niche through PERK-regulated endothelial DLL4 signaling to NOTCH3 on MSCs.