Regenerative function of myeloid derived suppressor cells in the damaged bone marrow endothelial niche - Project Abstract: Chemotherapy and radiotherapy treatments are the leading cause of acquired bone marrow (BM) failure and contribute to non-relapse mortality in many cancers. Several studies have pointed out that bone marrow failure is due to a deficiency in quality or engraftment of the hematopoietic stem and progenitor (HSPC). However, we propose that the overall survival and recovery of the BM niche microenvironment is equally important to the success of hematopoietic regeneration after preconditioning and HSPC transplant. We have established that robust Notch signaling is critical for survival and a timely recovery of the BM endothelial cells and by connection the hematopoietic system that relies on the functionality of this niche. Our findings suggest that a subset of progenitor myeloid derived suppressor cells (pro-MDSCs) express cKit, can upregulate the Notch ligand Jagged1 (Jag1), and play important roles in recovery of the niche by specifically promoting survival and regeneration of the endothelial cells in the BM. In addition, we propose a positive feedback mechanism where Notch activation in the endothelial cells actively promotes recruitment of damage resistant Jag1+ CCR2+ pro-MDSCs by production of CCL2. In this proposal we will determine the mechanistic aspects of how the interplay between BM niche cells and pro-MDSCs promotes hematopoietic recovery after chemo and radiation treatment. We will use cell-based therapy for recovery of the BM niche and cutting-edge bioengineering approaches to develop Jag1+ coated biomimetic nanoparticles (NPs) in cell-free treatments for acquired BM failure in relevant WT and transgenic model systems. In Aim 1, we will determine the mechanism by which Jagged1-expressing pro- MDSCs promote timely hematopoietic recovery after preconditioning. We will directly test the range of application of pro-MDSCs toward the recovery of the BM endothelial niche and endothelial cells in other tissues. To this end, we will design polymer-based NPs coated with lipid membrane overexpressing Jag1, determine their biodistribution and repair potential of the BM niche. In Aim 2, we will determine how endothelial cells promote their own survival and regeneration and ultimately support hematopoietic recovery by active recruitment of CCR2+ pro-MDSCs to the EC niche. We predict that following irradiation damage, BM endothelial cells recruit myeloid cells to sites of endothelial BM damage by secretion of chemokines. We will visualize interaction of pro- MDSCs with ECs in various tissues and measure pro-MDSC migration in several assays. We will test the effect of deletion of CCL2 in BM EC and CCR2 in donor pro-MDSCs during recovery. This project is multidisciplinary in that it will employ a combination of expertise in hematopoiesis, stem cell biology, and biomaterials to address the specific aims. The results will directly support the development of new therapeutic strategies to treat bone marrow failure.
