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Blood. 2015 Dec 24;126(26):2811-20. doi: 10.1182/blood-2015-07-659276. Epub 2015 Sep 18.

Hematopoietic stem cells develop in the absence of endothelial cadherin 5 expression.

Author information

1
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
2
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA;
3
Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA;
4
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA;
5
Max Planck Institute for Molecular Biomedicine, Münster, Germany;
6
Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
7
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
8
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA;
9
Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA; Howard Hughes Medical Institute, Boston, MA.
10
Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; and Howard Hughes Medical Institute, Boston, MA.
11
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;

Abstract

Rare endothelial cells in the aorta-gonad-mesonephros (AGM) transition into hematopoietic stem cells (HSCs) during embryonic development. Lineage tracing experiments indicate that HSCs emerge from cadherin 5 (Cdh5; vascular endothelial-cadherin)(+) endothelial precursors, and isolated populations of Cdh5(+) cells from mouse embryos and embryonic stem cells can be differentiated into hematopoietic cells. Cdh5 has also been widely implicated as a marker of AGM-derived hemogenic endothelial cells. Because Cdh5(-/-) mice embryos die before the first HSCs emerge, it is unknown whether Cdh5 has a direct role in HSC emergence. Our previous genetic screen yielded malbec (mlb(bw306)), a zebrafish mutant for cdh5, with normal embryonic and definitive blood. Using time-lapse confocal imaging, parabiotic surgical pairing of zebrafish embryos, and blastula transplantation assays, we show that HSCs emerge, migrate, engraft, and differentiate in the absence of cdh5 expression. By tracing Cdh5(-/-)green fluorescent protein (GFP)(+/+) cells in chimeric mice, we demonstrated that Cdh5(-/-)GFP(+/+) HSCs emerging from embryonic day 10.5 and 11.5 (E10.5 and E11.5) AGM or derived from E13.5 fetal liver not only differentiate into hematopoietic colonies but also engraft and reconstitute multilineage adult blood. We also developed a conditional mouse Cdh5 knockout (Cdh5(flox/flox):Scl-Cre-ER(T)) and demonstrated that multipotent hematopoietic colonies form despite the absence of Cdh5. These data establish that Cdh5, a marker of hemogenic endothelium in the AGM, is dispensable for the transition of hemogenic endothelium to HSCs.

PMID:
26385351
PMCID:
PMC4692141
DOI:
10.1182/blood-2015-07-659276
[Indexed for MEDLINE]
Free PMC Article

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