Haematopoietic stem cells derive directly from aortic endothelium during development (original) (raw)
- Letter
- Published: 14 February 2010
- Neil C. Chi3,4 na1,
- Buyung Santoso1,2,
- Shutian Teng1,2,
- Didier Y. R. Stainier4 &
- …
- David Traver1,2
Nature volume 464, pages 108–111 (2010)Cite this article
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Abstract
A major goal of regenerative medicine is to instruct formation of multipotent, tissue-specific stem cells from induced pluripotent stem cells (iPSCs) for cell replacement therapies. Generation of haematopoietic stem cells (HSCs) from iPSCs or embryonic stem cells (ESCs) is not currently possible, however, necessitating a better understanding of how HSCs normally arise during embryonic development. We previously showed that haematopoiesis occurs through four distinct waves during zebrafish development, with HSCs arising in the final wave in close association with the dorsal aorta. Recent reports have suggested that murine HSCs derive from haemogenic endothelial cells (ECs) lining the aortic floor1,2. Additional in vitro studies have similarly indicated that the haematopoietic progeny of ESCs arise through intermediates with endothelial potential3,4. Here we have used the unique strengths of the zebrafish embryo to image directly the generation of HSCs from the ventral wall of the dorsal aorta. Using combinations of fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry, we have identified and isolated the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. Finally, using a permanent lineage tracing strategy, we demonstrate that the HSCs generated from haemogenic endothelium are the lineal founders of the adult haematopoietic system.
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Acknowledgements
We thank S. Lin for providing kdrl:RFP animals. J.Y.B. was supported by the Irvington program of the Cancer Research Institute and by the California Institute for Regenerative Medicine (CIRM), N.C.C. by National Institutes of Health (NIH) HL074891, a Research and Education Foundation Award from GlaxoSmithKline and a Beginning Grant in Aid Award from the American Heart Association, B.S. by NIH F32DK752433, D.Y.R.S. by the Packard Foundation and NIH HL54737, and D.T. by a Scholar Award from the American Society of Hematology, a New Investigator Award from CIRM, and NIH DK074482.
Author Contributions J.Y.B., N.C.C. and D.T. designed experiments. J.Y.B. and D.T. wrote the manuscript, with key input from N.C.C. and D.Y.R.S.; J.Y.B. performed experiments. B.S. and S.T. generated and characterized the bactin:switch reporter line. N.C.C. and D.Y.R.S. generated kdrl:Cre and kdrl:memCherry transgenic lines.
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Author notes
- Julien Y. Bertrand and Neil C. Chi: These authors contributed equally to this work.
Authors and Affiliations
- Department of Cellular and Molecular Medicine,,
Julien Y. Bertrand, Buyung Santoso, Shutian Teng & David Traver - Section of Cell and Developmental Biology,,
Julien Y. Bertrand, Buyung Santoso, Shutian Teng & David Traver - Department of Medicine, University of California, San Diego, La Jolla, California 92093-0380, USA,
Neil C. Chi - Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, USA,
Neil C. Chi & Didier Y. R. Stainier
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- Julien Y. Bertrand
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Correspondence toDavid Traver.
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Bertrand, J., Chi, N., Santoso, B. et al. Haematopoietic stem cells derive directly from aortic endothelium during development.Nature 464, 108–111 (2010). https://doi.org/10.1038/nature08738
- Received: 30 July 2009
- Accepted: 09 December 2009
- Published: 14 February 2010
- Issue Date: 04 March 2010
- DOI: https://doi.org/10.1038/nature08738
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Editorial Summary
Blood stem cell creation
In zebrafish, haematopoietic stem cells (HSCs) arise from the dorsal aorta of the embryo. In vitro studies have suggested that there are in the dorsal aorta a population of intermediate progenitors that can give rise to both endothelial (or blood vessel lineage) and blood cells. In this issue, two groups present images showing the birth of HSCs from the ventral wall of the dorsal aorta in live zebrafish embryos. Bertrand et al. combined fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry to identify and isolate the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. They also show that the HSCs generated from this haemogenic endothelium are the lineal founders of virtually all of the adult haematopoietic system. Karima Kissa and Philippe Herbomel similarly use imaging of live zebrafish to show HSCs emerge directly from the aorta floor, They show this process that does not involve cell division but movement of single endothelial cells out of the aorta ventral wall into the sub-aortic space, where they transform into haematopoietic cells. They call this new type of cell behaviour endothelial haematopoietic transition (EHT). In a third report, Boisset et al. confirm that this process also occurs in mice, using a dissection procedure to visualize the deeply located aorta. They showed de novo emergence of phenotypically defined HSCs directly from ventral aortic haemogenic endothelial cells.