Jagged1⁺ Myeloid-Derived Suppressor Cells Are Required for Recovery of the Hematopoietic Bone Marrow Niche after Myelosuppression

Myelosuppressive treatments such as chemotherapy and radiotherapy are widely used to treat a variety of hematopoietic diseases and disorders, however current treatment regiments induce broad cytotoxicity illustrated by off-target tissue damage. In order for timely recovery of vascular and hematopoietic function, bone marrow (BM) endothelial cells must regenerate following myelosuppression. The identity and mechanism by which myelosuppressive-resistant cells that trigger endothelial regeneration in the damaged BM microenvironment are unknown. In the present study, we show that Jagged1 (Jag1) expression was significantly upregulated in various hematopoietic populations, particularly in myeloid-derived suppressor cells (MDSCs), following myelosuppression. By crossing Jag1conditional knockoutmice with Vav1-Cre driver mice, we generated the Jag1^f/fVavCre⁺ strain that specific deletes Jag1 in hematopoietic cells. We demonstrate that loss of hematopoietic Jag1 does not affect numbers and function of hematopoietic stem and progenitor cells (HSPCs) under homeostatic condition, but Jag1^f/fVavCre⁺ mice rapidly succumb to both chemo- and radio-therapeutic stress exhibited by severe pancytopenia, very limited endothelial regeneration, and rapid weight loss and morbidity. Full recovery can be achieved by adoptive transfer of WT bone marrow MDSCs, which we show can efficiently rescue the severe phenotypes of Jag1^f/fVavCre⁺ by improving endothelial cell recovery and hematopoietic niche regeneration. Using reporter models, we show that robust Notch pathway activation in endothelial cells is mediated by Jag1⁺MDSCs. This leads to hematopoietic recovery due to proliferation and elevated numbers of HSPCs in Jag1^f/fVavCre⁺ mice. Treatment with Jag1-coated nanoparticles similarly rescues viability of the BM endothelial cells. Our findings indicate that hematopoietic Jag1 is essential in accelerating niche regeneration and hematopoietic recovery and is a potential therapeutic target in ameliorating damage from multiple myelosuppressive treatments.

No relevant conflicts of interest to declare.