Abstract
Although exceptionally high radiation dose-rates are currently attaining clinical feasibility, there have been relatively few studies reporting the biological consequences of these dose-rates in hematopoietic cell transplant (HCT). In zebrafish models of HCT, preconditioning before transplant is typically achieved through radiation alone. We report the comparison of outcomes in adult zebrafish irradiated with 20Gy at either 25 or 800 cGy/min in the context of experimental HCT. In non-transplanted irradiated fish we observed no substantial differences between dose-rate groups as assessed by fish mortality, cell death in the kidney, endogenous hematopoietic reconstitution, or gene expression levels of p53 and ddb2 (damage-specific DNA binding protein 2) in the kidney. However, following HCT, recipients conditioned with the higher dose rate showed significantly improved donor-derived engraftment at 9 days post transplant (p≤0.0001), and improved engraftment persisted at 31 days post transplant. Analysis for sdf-1a expression, as well as transplant of hematopoietic cells from cxcr4b −/− zebrafish, (odysseus), cumulatively suggest that the sdf-1a/cxcr4b axis is not required of donor-derived cells for the observed dose-rate effect on engraftment. Overall, the adult zebrafish model of HCT indicates that exceptionally high radiation dose-rates can impact HCT outcome, and offers a new system for radiobiological and mechanistic interrogation of this phenomenon. Key words: Radiation dose rate, Total Marrow Irradiation (TMI), Total body irradiation (TBI), SDF-1, Zebrafish, hematopoietic cell transplant.
Highlights
Radiation preconditioning is often used to prepare patients for hematopoietic cell transplant (HCT), and is a common preconditioning method in animal models used to study the mechanisms of hematopoietic cell homing and engraftment
800 cGy/min dose-rates on fish irradiated with 20 Gy, we performed survival, cell death, and myelosuppression studies on irradiated, non-transplanted adult Wild type (WT) zebrafish
Flow cytometry analysis of whole kidney marrow cells (WKM) isolated from WT fish at multiple time points following radiation revealed hematopoietic cell loss and subsequent recovery, as has been previously reported to occur following sublethal irradiation of fish [12]
Summary
Radiation preconditioning is often used to prepare patients for hematopoietic cell transplant (HCT), and is a common preconditioning method in animal models used to study the mechanisms of hematopoietic cell homing and engraftment. Despite reductions in off-target toxicities associated with lowered doserates, delivery of a desired dose at a low rate during a single treatment session could present logistical drawbacks due to prohibitively long delivery times [6] Recognition of this helped to promote fractionated delivery, with goals to minimize organ toxicity, while leaving hematopoietic ablation effects essentially intact [6]. New advances in conformal radiation allow exceptionally high dose-rates targeted to the bone marrow alone, while sparing non-target organs [7] This makes it possible to consider the therapeutic outcomes of high dose-rates that were traditionally considered inadvisable, and prompts renewed interest in refining our understanding of radiation doserate effects as they relate to HCT and engraftment
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