Notch Signaling Mitigates Chemotherapy Toxicity By Accelerating Hematopoietic Stem Cells Proliferation Via C-Myc

The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. Here, we showed that disruption of Notch signaling aggravated chemotherapy-induced myelosuppression in inducible genetic mice. Conversely, Notch activation correlated positively with clinical HSC engraftment. We used endothelial-targeted chimeric Notch ligand Delta-like 1 (D1R) to activate Notch signaling in hematopoietic stem/progenitor cells through micro-environmental cellular contact. Recombinant protein D1R contributed to the recovery of the HSC pool and sustained HSC vitality in response to various chemotherapeutic agents in vivo. Mechanistically, D1R treatment promoted HSC proliferation transiently, prevented HSC exhaustion, correlated with activation of the downstream phosphoinositide 3-kinase (PI3K)/extracellular-signal-regulated kinase (ERK)/ BCL2 associated agonist of cell death (BAD) signaling axis during regeneration, and partially mediated upregulation of c-Myc in HSCs. These data reveal an unrecognized role for Notch signaling in promoting HSC repopulation after myelosuppressive chemotherapy and offer a new therapeutic approach to mitigate chemotherapy-induced injury.