Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis

Scott T. Avecilla, Koichi Hattori, Beate Heissig, Rafael Tejada, Fang Liao, Koji Shido, David K. Jin, Sergio Dias, Fan Zhang, Travis E. Hartman, Neil R. Hackett, Ronald G. Crystal, Larry Witte, Daniel J. Hicklin, Peter Bohlen, Dan Eaton, David Lyden, Fredric De Sauvage, Shahin Rafii

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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.

Original languageEnglish
Pages (from-to)64-71
Number of pages8
JournalNature Medicine
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Jan 2004

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Avecilla, S. T., Hattori, K., Heissig, B., Tejada, R., Liao, F., Shido, K., Jin, D. K., Dias, S., Zhang, F., Hartman, T. E., Hackett, N. R., Crystal, R. G., Witte, L., Hicklin, D. J., Bohlen, P., Eaton, D., Lyden, D., De Sauvage, F., & Rafii, S. (2004). Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nature Medicine, 10(1), 64-71. https://doi.org/10.1038/nm973