title: Definitive Hematopoiesis in the Yolk Sac Emerges from Wnt-Responsive Hemogenic Endothelium Independently of Circulation and Arterial Identity.
abstract: Adult-repopulating hematopoietic stem cells (HSCs) emerge in low numbers in the midgestation mouse embryo from a subset of arterial endothelium, through an endothelial-to-hematopoietic transition. HSC-producing arterial hemogenic endothelium relies on the establishment of embryonic blood flow and arterial identity, and requires β-catenin signaling. Specified prior to and during the formation of these initial HSCs are thousands of yolk sac-derived erythro-myeloid progenitors (EMPs). EMPs ensure embryonic survival prior to the establishment of a permanent hematopoietic system, and provide subsets of long-lived tissue macrophages. While an endothelial origin for these HSC-independent definitive progenitors is also accepted, the spatial location and temporal output of yolk sac hemogenic endothelium over developmental time remain undefined. We performed a spatiotemporal analysis of EMP emergence, and document the morphological steps of the endothelial-to-hematopoietic transition. Emergence of rounded EMPs from polygonal clusters of Kit(+) cells initiates prior to the establishment of arborized arterial and venous vasculature in the yolk sac. Interestingly, Kit(+) polygonal clusters are detected in both arterial and venous vessels after remodeling. To determine whether there are similar mechanisms regulating the specification of EMPs with other angiogenic signals regulating adult-repopulating HSCs, we investigated the role of embryonic blood flow and Wnt/β-catenin signaling during EMP emergence. In embryos lacking a functional circulation, rounded Kit(+) EMPs still fully emerge from unremodeled yolk sac vasculature. In contrast, canonical Wnt signaling appears to be a common mechanism regulating hematopoietic emergence from hemogenic endothelium. These data illustrate the heterogeneity in hematopoietic output and spatiotemporal regulation of primary embryonic hemogenic endothelium.
authors.affiliation: Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York, USA.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Frame
authors.affiliation: Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Fegan
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: McGrath
authors.affiliation: Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: James
authors.initials: J
authors.lastname: Palis
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051153:Wnt Proteins / Q000378:metabolism*; D015017:Yolk Sac / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins
keywords: Embryo; Endothelial cell; Hemangioblast; Hematopoiesis; Hematopoietic progenitors; Hematopoietic stem cells; Vascular development