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Nat Cell Biol. 2017 Jan;19(1):17-27. doi: 10.1038/ncb3444. Epub 2016 Nov 21.

Clonal fate mapping quantifies the number of haematopoietic stem cells that arise during development.

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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.
Biological and Biomedical Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.
Section of Cell and Developmental Biology, University of California at San Diego, La Jolla, California 92093, USA.
Biotechnology Center and Center for Regenerative Therapies Dresden, Dresden University of Technology, Tatzberg 47-49, 01307 Dresden, Germany.
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland.
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093-0380, USA.


Haematopoietic stem cells (HSCs) arise in the developing aorta during embryogenesis. The number of HSC clones born has been estimated through transplantation, but experimental approaches to assess the absolute number of forming HSCs in a native setting have remained challenging. Here, we applied single-cell and clonal analysis of HSCs in zebrafish to quantify developing HSCs. Targeting creERT2 in developing cd41:eGFP+ HSCs enabled long-term assessment of their blood contribution. We also applied the Brainbow-based multicolour Zebrabow system with drl:creERT2 that is active in early haematopoiesis to induce heritable colour barcoding unique to each HSC and its progeny. Our findings reveal that approximately 21 HSC clones exist prior to HSC emergence and 30 clones are present during peak production from aortic endothelium. Our methods further reveal that stress haematopoiesis, including sublethal irradiation and transplantation, reduces clonal diversity. Our findings provide quantitative insights into the early clonal events that regulate haematopoietic development.

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