title: R-spondin 1 is required for specification of hematopoietic stem cells through Wnt16 and Vegfa signaling pathways.
abstract: Hematopoietic stem cells (HSCs) are the therapeutic component of bone marrow transplants, but finding immune-compatible donors limits treatment availability and efficacy. Recapitulation of endogenous specification during development is a promising approach to directing HSC specificationin vitro, but current protocols are not capable of generating authentic HSCs with high efficiency. Across phyla, HSCs arise from hemogenic endothelium in the ventral floor of the dorsal aorta concurrent with arteriovenous specification and intersegmental vessel (ISV) sprouting, processes regulated by Notch and Wnt. We hypothesized that coordination of HSC specification with vessel patterning might involve modulatory regulatory factors such as R-spondin 1 (Rspo1), an extracellular protein that enhances β-catenin-dependent Wnt signaling and has previously been shown to regulate ISV patterning. We find that Rspo1 is required for HSC specification through control of parallel signaling pathways controlling HSC specification: Wnt16/DeltaC/DeltaD and Vegfa/Tgfβ1. Our results define Rspo1 as a key upstream regulator of two crucial pathways necessary for HSC specification.
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jamie R
authors.identifier: 0000-0003-4668-0606
authors.initials: JR
authors.lastname: Genthe
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA wilson.clements@stjude.org.
authors.forename: Wilson K
authors.identifier: 0000-0003-4365-9553
authors.initials: WK
authors.lastname: Clements
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000378:metabolism; D019521:Body Patterning; D002454:Cell Differentiation; D003001:Cloning, Molecular; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055018:Hemangioblasts / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008297:Male; D009154:Mutation; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction; D019699:Thrombospondins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C559646:wnt16 protein, zebrafish
keywords: HSCs; Rspo1; Vegfaa; Wnt signaling; Zebrafish