@article{5e800e525e274f9c80b8ee961c04058e,
title = "The transcriptional landscape of hematopoietic stem cell ontogeny",
abstract = "Transcriptome analysis of adult hematopoietic stem cells (HSCs) and their progeny has revealed mechanisms of blood differentiation and leukemogenesis, but a similar analysis of HSC development is lacking. Here, we acquired the transcriptomes of developing HSCs purified from >2,500 murine embryos and adult mice. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs undergoing specification, and definitive HSCs. We applied a network-biology- based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development and functionally validated candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knockdown in zebrafish embryos. Moreover, we found that HSCs from in vitro differentiated embryonic stem cells closely resemble definitive HSCs, yet lack a Notch-signaling signature, likely accounting for their defective lymphopoiesis. Our analysis and web resource will enhance efforts to identify regulators of HSC ontogeny and facilitate the engineering of hematopoietic specification.",
author = "Shannon McKinney-Freeman and Patrick Cahan and Hu Li and Lacadie, {Scott A.} and Huang, {Hsuan Ting} and Matthew Curran and Sabine Loewer and Olaia Naveiras and Kathrein, {Katie L.} and Martina Konantz and Langdon, {Erin M.} and Claudia Lengerke and Zon, {Leonard I.} and Collins, {James J.} and Daley, {George Q.}",
note = "Funding Information: We thank M.W. Lensch for helpful discussions and critical review of the manuscript, N. Gerry for assistance with gene expression arrays, and J. Daley and S. Lazo-Kallanian of the Dana Farber Cancer Institute (Boston, MA) and Richard Ashman and Jim Houston of St. Jude Children{\textquoteright}s Research Hospital (Memphis, TN) for expertise in cell sorting and flow cytometry. Fluidigm experiments were performed by the Molecular Genetics Core Facility at Children{\textquoteright}s Hospital Boston supported by NIH-P50-NS40828 and NIH-P30-HD18655. S.M.F. was supported by NIH grant K01 DK080846. G.Q.D. is supported by grants from the NIH (RO1-DK70055, RO1-DK59279, UO1-HL100001, Progenitor cell biology consortium, R24-DK092760, and special funds from the ARRA stimulus package RC2-HL102815), the Roche Foundation for Anemia Research, Alex{\textquoteright}s Lemonade Stand, and the Harvard Stem Cell Institute. G.Q.D. is an affiliate member of the Broad Institute, a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and an investigator of the Manton Center for Orphan Disease Research. P.C. is supported by grants T32HL007623 and 2T32HL66987-11 from the NHLBI. G.Q.D., L.I.Z., and J.J.C. are investigators of the Howard Hughes Medical Institute. L.I.Z. is supported by HHMI and NIH NIDDK 1R24DK092760-01. J.J.C. and H.L. are supported by Howard Hughes Medical Institute, SysCODE (Systems-based Consortium for Organ Design & Engineering), and NIH grant # RL1DE019021, and H.L. is supported by Boston University Clinical and Translational Science Institute (CTSI) grant # UL1-TR000157. C.L. was supported by grants from the Deutsche Krebshilfe (Max Eder Program) and the Deutsche Forschungsgemeinschaft (SFB773). L.I.Z. is a founder and stock holder of Fate, Inc. and a scientific advisor for Stemgent. ",
year = "2012",
month = nov,
day = "2",
doi = "10.1016/j.stem.2012.07.018",
language = "English (US)",
volume = "11",
pages = "701--714",
journal = "Cell stem cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",
}