@article{71cf5264b7664feb81245078ed9efeae,
title = "Hematopoietic stem cells develop in the absence of endothelial cadherin 5 expression",
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-derivedhemogenic 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 (mlbbw306), 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 (Cdh5flox/flox:Scl-Cre-ERT) 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 ofhemogenic endotheliumto HSCs.",
author = "Heidi Anderson and Patch, {Taylor C.} and Reddy, {Pavankumar N.G.} and Hagedorn, {Elliott J.} and Kim, {Peter G.} and Soltis, {Kathleen A.} and Chen, {Michael J.} and Tamplin, {Owen J.} and Maike Frye and MacLean, {Glenn A.} and Kathleen H{\"u}bner and Bauer, {Daniel E.} and Kanki, {John P.} and Guillaume Vogin and Huston, {Nicholas C.} and Minh Nguyen and Yuko Fujiwara and Paw, {Barry H.} and Dietmar Vestweber and Zon, {Leonard I.} and Orkin, {Stuart H.} and Daley, {George Q.} and Shah, {Dhvanit I.}",
note = "Funding Information: The authors are grateful toKathryn Crosier, Philip Crosier, Jeff Cooney, Iman Schultz, Matthew King, Yi Zhou, Christian Lawrence, Eric L. Pierce, BenjanimS. Brigham, Jessica Collantonio, Spencer K. Heggers, and Michelle Cassim for their technical help and/or for providing reagents. D.I.S. is supported by grants from the American Society of Hematology, the Cooley''s Anemia Foundation, and the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants (K01DK085217 and R03DK100672). H.A. is supported by a fellowship from the Sigrid Juselius Foundation. E.J.H. is supported by a fellowship from the Helen Hay Whitney Foundation. P.N.G.R. is supported by a fellowship from the American Society of Hematology. O.J.T. is supported by a fellowship fromthe American Society of Hematology. G.A.M. is supported by a fellowship from the Alex''s Lemonade Stand Foundation. D.E.B. is supported by a grant from the NIH, NIDDK (K08DK093705). B.H.P. is supported by a grant fromthe NIH, National Heart, Lung, and Blood Institute (P01HL032262). M.F. and D.V. are supported by grants from the Deutsche Forschungsgemeinschaft and the Max Planck Society. L.I.Z. is supported by grants from the NIH National Cancer Institute (R01CA103846) and National Heart, Lung, and Blood Institute (P01HL032262 and R01HL04880). S.H.O. is supported by grants from the NIH NIDDK (P30DK049216) and National Heart, Lung, and Blood Institute (R01HL032259 and P01HL032262). G.Q.D. is supported by grants from the NIH National Heart, Lung and Blood Institute (Progenitor Cell Biology Consortium UO1-HL100001) and NIDDK (R24DK092760), the Alex''s Lemonade Foundation, and the Boston Children''s Hospital Stem Cell Program. L.I.Z., S.H.O., and G.Q.D. are investigators of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2015 by The American Society of Hematology.",
year = "2015",
month = dec,
day = "24",
doi = "10.1182/blood-2015-07-659276",
language = "English",
volume = "126",
pages = "2811--2820",
journal = "Blood",
issn = "0006-4971",
publisher = "Elsevier BV",
number = "26",
}