Notch-Expanded Murine Hematopoietic Stem and Progenitor Cells Mitigate Death From Lethal Radiation and Convey Immune Tolerance in Mismatched Recipients.

: The hematopoietic syndrome of acute radiation syndrome (h-ARS) is characterized by severe bone marrow aplasia, resulting in a significant risk for bleeding, infections, and death. To date, clinical management of h-ARS is limited to supportive care dictated by the level of radiation exposure, with a high incidence of mortality in those exposed to high radiation doses. The ideal therapeutic agent would be an immediately available, easily distributable single-agent therapy capable of rapid in vivo hematopoietic reconstitution until recovery of autologous hematopoiesis occurs. Using a murine model of h-ARS, we herein demonstrate that infusion of ex vivo expanded murine hematopoietic stem and progenitor cells (HSPCs) into major histocompatibility complex mismatched recipient mice exposed to a lethal dose of ionizing radiation (IR) led to rapid myeloid recovery and improved survival. Survival benefit was significant in a dose-dependent manner even when infusion of the expanded cell therapy was delayed 3 days after lethal IR exposure. Most surviving mice (80%) demonstrated long-term in vivo persistence of donor T cells at low levels, and none had evidence of graft versus host disease. Furthermore, survival of donor-derived skin grafts was significantly prolonged in recipients rescued from h-ARS by infusion of the mismatched expanded cell product. These findings provide evidence that ex vivo expanded mismatched HSPCs can provide rapid, high-level hematopoietic reconstitution, mitigate IR-induced mortality, and convey donor-specific immune tolerance in a murine h-ARS model.

SIGNIFICANCE: There is an urgent need to develop a therapeutic agent for the treatment or supportive care of the hematopoietic syndrome of acute radiation syndrome (h-ARS). This study reports on the infusion of mismatched cryopreserved ex vivo mouse hematopoietic stem and progenitor cells (HSPCs), expanded in the presence of Notch ligand, after a lethal dose of ionizing radiation (IR). The results were rapid donor engraftment, mitigated IR-induced toxicity, and improved survival in a dose-dependent manner. Moreover, these cells induced donor-specific immune tolerance, resulting in longer survival of donor skin allografts. These findings reinforce that cord blood-derived HSPCs, expanded ex vivo by using Notch ligand, offer a powerful therapeutic tool for victims of h-ARS and potentially for recipients of organ transplants.