title: Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis.
abstract: The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Cornell University Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Avecilla
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.forename: Rafael
authors.initials: R
authors.lastname: Tejada
authors.forename: Fang
authors.initials: F
authors.lastname: Liao
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.forename: David K
authors.initials: DK
authors.lastname: Jin
authors.forename: Sergio
authors.initials: S
authors.lastname: Dias
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Travis E
authors.initials: TE
authors.lastname: Hartman
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.forename: Larry
authors.initials: L
authors.lastname: Witte
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Peter
authors.initials: P
authors.lastname: Bohlen
authors.forename: Dan
authors.initials: D
authors.lastname: Eaton
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Fredric
authors.initials: F
authors.lastname: de Sauvage
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001853:Bone Marrow / Q000098:blood supply*; D015820:Cadherins / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018925:Chemokines / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology; D053628:Receptors, Thrombopoietin; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000235:genetics / Q000502:physiology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018925:Chemokines; D015513:Oncogene Proteins; D019718:Receptors, CXCR4; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin; D000099152:Cadherin 5; C481270:Mpl protein, mouse