Effect of radiation dose-rate on hematopoietic cell engraftment in adult zebrafish.
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 20 Gy 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.
Department of Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota Medical School, Minneapolis, Minnesota.
Tiffany J
TJ
Glass
Susanta K
SK
Hui
Bruce R
BR
Blazar
Troy C
TC
Lund
D000818:Animals; D016923:Cell Death / Q000528:radiation effects; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D015870:Gene Expression; D006085:Graft Survival / Q000235:genetics / Q000276:immunology / Q000528:radiation effects*; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology; D014916:Whole-Body Irradiation; D015027:Zebrafish / Q000235:genetics / Q000276:immunology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000276:immunology
C471276:CXCR4b protein, zebrafish; D054377:Chemokine CXCL12; C534218:DDB2 protein, zebrafish; D004268:DNA-Binding Proteins; D019718:Receptors, CXCR4; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins