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.

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Figure 1: SDF-1 and FGF-4 restore platelet counts in TPO- or c-Mpl-deficient mice.
Figure 2: SDF-1 and FGF-4 increase interaction of megakaryocytes with sinusoidal BMECs.
Figure 3: SDF-1 and FGF-4 induce generation of polyploid megakaryocytes by increasing interaction with BMECs.
Figure 4: Targeted disruption of the vascular niche by blocking VE-cadherin impairs megakaryocyte adhesion to BMECs and thrombopoiesis.
Figure 5: Inhibition of CXCR4 and VE-cadherin signaling blocks physiological reconstitution of thrombopoiesis.
Figure 6: Chemokines ameliorate chemotherapy-induced thrombocytopenia in vivo.

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Acknowledgements

S.R. is supported by the National Heart, Lung, Blood Institute (R01 grants HL61849, HL66592, HL67839 and HL59312), the American Cancer Society (101396) and the Leukemia and Lymphoma Society. S.T.A. is supported by the W.M. Keck Foundation, the Dr. Ezekiel Marion Foster Medical Scientist Fellowship and National Institutes of Health MSTP grant GM07739 (Cornell/Rockefeller/ Sloan-Kettering MD-PhD program). D.L. is supported by National Cancer Institute grant ROI-CA-98234.

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Correspondence to Shahin Rafii.

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The monoclonal antibody to VE-cadherin was generated by ImClone Systems.F.L., L.W., D.H.and P.E.are employees of ImClone Systems.S.R. received support for unrelated leukemia research from ImClone Systems.

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Avecilla, S., Hattori, K., Heissig, B. et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 10, 64–71 (2004). https://doi.org/10.1038/nm973

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