Impacts of SDF-1 and radiation dose-rate in an adult zebrafish model of hematopoietic cell transplant

University of Minnesota Ph.D. dissertation. May 2013. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Bruce Blazar. 1 computer file (PDF); v, 91 pages.Despite a history of refinements, Hematopoietic Cell Transplant (HCT) remains a potentially difficult treatment that can have high risks for complications and mortality. We used adult zebrafish models of HCT to study two broad biological processes that occur during HCT; homing and early donor-derived hematopoietic reconstitution. In the first case, we validated the adult zebrafish model for the study of the chemokine SDF-1 in HCT, developed a transgenic sdf-1 reporter zebrafish line, and used it to determine sites of high sdf-1 expression in recipient organisms. These sites were discovered both in the hematopoietic tissue as well as in previously un-described structures throughout the skin, and were found to consistently attract donor-derived cells after transplant. Ultimately, this allowed the identification of new putative HSC-niche cells which can be isolated with relative ease. Secondly, we assessed the effects of high conditioning radiation dose-rates on the process of hematopoietic engraftment after transplant. In groups of adult zebrafish given the same total dose of preconditioning radiation, we found that recipients irradiated at a high rate show significantly faster engraftment compared to those irradiated at a lower rate. Insights offered by this work will contribute to future efforts identifying endogenous factors promoting rapid engraftment, as well as to future reassessments of therapeutic opportunities offered by biologically informed refinements of preconditioning radiation strategies