Year 1

During the past year, we have made substantial progress in the discovery and translation of niche-derived growth factors which stimulate hematopoietic stem cell regeneration. In one aim, we interrogated the activity of bone marrow niche cells which are responsible for the generation of bone cells which reside adjacent to hematopoietic stem cells. We discovered that deletion of cell death proteins from bone forming niche cells caused the protection of hematopoietic stem cells in mice following radiation exposure. We subsequently screened the bone forming cells for secreted proteins and discovered a soluble protein which is produced by bone forming cells and was strongly associated with the regeneration of hematopoietic stem cells. Further, treatment of hematopoietic stem cells with this bone-derived factor rescued hematopoietic stem cells from radiation-induced depletion in vitro. Systemic treatment of mice following lethal dose irradiation with this bone-derived factor potently accelerated the regeneration of hematoopoietic stem cells in vivo and markedly increased the survival of irradiated mice compared to controls. In complementary studies, we discovered a novel transmembrane receptor which is highly expressed on mouse and human hematopoietic stem cells and have shown that genetic deletion of this receptor significantly increased hematopoietic stem cell repopulating capacity following transplantation into recipient mice. This led to examination of the structure-activity-relationships of candidate small molecules with the transmembrane receptor. Based on this analysis, we functionally screened several candidate modulators of this receptor for activity against hematopoietic stem cells in culture. One candidate small molecule caused a significant expansion of hematopoietic stem cells in culture. Subsequently, we irradiated wild type mice with a lethal dose of irradiation and demonstrated that systemic administration of this candidate receptor modulator caused a significant acceleration in the recovery of hematopoietic stem cells in vivo, as well as the marked increase in survival of irradiated mice compared to controls. These 2 complementary studies provide the foundation for the development and translation of these hematopoietic regenerative growth factors for therapeutic purposes in the coming year.