Nature Medicine10, 64 - 71 (2004)
Published online: 21 December 2003; | doi:10.1038/nm973
Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis
Scott T Avecilla1, 6, Koichi Hattori1, 6, Beate Heissig1, 6, Rafael Tejada1, Fang Liao2, Koji Shido1, David K Jin1, Sergio Dias1, Fan Zhang1, 4, Travis E Hartman4, Neil R Hackett4, Ronald G Crystal4, Larry Witte2, Daniel J. Hicklin2, Peter Bohlen2, Dan Eaton3, David Lyden5, Fredric de Sauvage3
& Shahin Rafii1, 4
1
Department of Medicine, Division of Hematology-Oncology, Cornell University Medical College, 1300 York Avenue, New York, New York 10021, USA.
2
ImClone Systems, 180 Varick Street, New York, New York 10014, USA.
3
Genentech, One DNA Way, South San Francisco, California 94404, USA.
4
Department of Genetic Medicine, Cornell University Medical College, 1300 York Avenue, New York, New York 10021, USA.
5
Departments of Pediatrics and the Children's Blood Foundation Laboratories, Cornell University Medical College, 1300 York Avenue, New York, New York 10021, USA.
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.
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