Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis.
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.
Avecilla
Scott T
ST
Department of Medicine, Division of Hematology-Oncology, Cornell University Medical College, 1300 York Avenue, New York, New York 10021, USA.
Hattori
Koichi
K
Heissig
Beate
B
Tejada
Rafael
R
Liao
Fang
F
Shido
Koji
K
Jin
David K
DK
Dias
Sergio
S
Zhang
Fan
F
Hartman
Travis E
TE
Hackett
Neil R
NR
Crystal
Ronald G
RG
Witte
Larry
L
Hicklin
Daniel J
DJ
Bohlen
Peter
P
Eaton
Dan
D
Lyden
David
D
de Sauvage
Fredric
F
Rafii
Shahin
S
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
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