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Dis Model Mech. 2018 Sep 28. pii: dmm.034876. doi: 10.1242/dmm.034876. [Epub ahead of print]

Generation of mouse-zebrafish hematopoietic tissue chimeric embryos for hematopoiesis and host-pathogen interaction studies.

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Center for Genome Regulation, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
Immunology and Allergy, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.
Center for Genome Regulation, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
Department of Cell Biology and Human Anatomy, University of California, Davis, Davis CA, 95616, USA.


Xenografts of the hematopoietic system are extremely useful as disease models and for translational research. Zebrafish xenografts have been widely used to monitor blood cancer cell dissemination and homing due to the optical clarity of embryos and larvae, which allow unrestricted in vivo visualization of migratory events. Here, we have developed a xenotransplantation technique that transiently generates hundreds of hematopoietic tissue chimeric embryos by transplanting murine bone marrow cells into zebrafish blastulae. In contrast to previous methods, this procedure allows mammalian cell integration into the fish developmental hematopoietic program, which results in chimeric animals containing distinct phenotypes of murine blood cells in both circulation and the hematopoietic niche. Murine cells in chimeric animals express antigens related to i) hematopoietic stem and progenitor cells, ii) active cell proliferation and iii) myeloid cell lineages. We verified the utility of this method by monitoring zebrafish chimeras during development using in vivo non-invasive imaging to show novel murine cell behaviors, such as homing to primitive and definitive hematopoietic tissues, dynamic hematopoietic cell-vascular endothelial and hematopoietic cell-niche interactions, and response to bacterial infection. Overall, transplantation into the zebrafish blastula provides a useful method that simplifies the generation of numerous chimeric animals and expands the range of murine cell behaviors that can be studied in zebrafish chimeras. In addition, integration of murine cells into the host hematopoietic system during development suggests highly conserved molecular mechanisms of hematopoiesis between zebrafish and mammals.


Cell migration; Hematopoiesis; Host-pathogen interactions; Live imaging; Xenotransplantation; Zebrafish

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