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.
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: McKinney-Freeman
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lacadie
authors.forename: Hsuan-Ting
authors.initials: HT
authors.lastname: Huang
authors.forename: Matthew
authors.initials: M
authors.lastname: Curran
authors.forename: Sabine
authors.initials: S
authors.lastname: Loewer
authors.forename: Olaia
authors.initials: O
authors.lastname: Naveiras
authors.forename: Katie L
authors.initials: KL
authors.lastname: Kathrein
authors.forename: Martina
authors.initials: M
authors.lastname: Konantz
authors.forename: Erin M
authors.initials: EM
authors.lastname: Langdon
authors.forename: Claudia
authors.initials: C
authors.lastname: Lengerke
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D015017:Yolk Sac / Q000166:cytology; D015027:Zebrafish