title: CD34(-) cells at the apex of the human hematopoietic stem cell hierarchy have distinctive cellular and molecular signatures.
abstract: In addition to well-characterized CD34(+) hematopoietic stem and progenitor cells (HSPCs), the human hematopoietic stem cell (HSC) hierarchy contains a rare CD34(-) population with severe combined immunodeficiency-repopulating capacity. However, little is known about the molecular characteristics of these CD34(-) cells or their relationship to the CD34(+) populations. Here, we show that the self-renewing Lin(-)CD34(-)CD38(-)CD93(hi) population contains cells that not only function as HSCs, but can also be placed above the CD34(+) populations in the hematopoietic hierarchy. These cells have an active Notch pathway, in which signaling through Delta4 is crucial for maintenance of the primitive state, and combined signals from Jagged1 and TGF-β are important in controlling its quiescence. They are also refractory to proliferative signals and show a repressed canonical Wnt pathway, in part regulated by Notch. Overall, therefore, CD34(-) cells represent an immature and quiescent human HSC population maintained through a distinctive network of cellular signaling interactions.
authors.affiliation: Haematopoietic Stem Cell Lab, Cancer Research UK. fernando.afonso@cancer.org.uk
authors.forename: Fernando
authors.initials: F
authors.lastname: Anjos-Afonso
authors.forename: Erin
authors.initials: E
authors.lastname: Currie
authors.forename: Hector G
authors.initials: HG
authors.lastname: Palmer
authors.forename: Katie E
authors.initials: KE
authors.lastname: Foster
authors.forename: David C
authors.initials: DC
authors.lastname: Taussig
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D018952:Antigens, CD34; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; C032402:complement 1q receptor; D051997:ADP-ribosyl Cyclase 1