[465] Chemokine-Mediated Enhanced Megakaryocyte Motility Is Essential and Sufficient for Thrombopoietin-Independent Thrombopoiesis.
Koichi Hattori, Beate Heissig, Masahiro Goshima, Dan Eaton, Barbara Ferris, Rafael Tejeda, Isao Nagaoka, Ron G. Crystal, David Lyden, Fred J. de Sauvage, Shahin Rafii. Cornell University Medical College, NY, NY, USA; Juntendo University, Tokyo, Japan; Genentech, Inc., SF, CA, USA
With the cloning and characterization of thrombopoietin (TPO) in 1997, TPO was identified as a principal mitogenic and differentiation factor for megakaryopoiesis and thrombopoiesis. However, despite the discovery of TPO, the exact mechanism of platelet production is still not known. TPO deficient (TPO-/-) or TPO-receptor (C-mpl) deficient (-/-) mice, despite having 80% reduction in the megakaryocyte and platelet counts, have no apparent hemorrhagic defects. To date, all the known factors that promote megakaryocyte maturation such as IL-3, IL-6, GM-CSF and IL-11 failed to induce platelet increase in TPO-/- mice. Moreover, numerous clinical trials have shown that recombinant TPO is ineffective in restoring platelet production in patients treated with marrow suppressive agents. Collectively these data have raised the possibility that other factors, rather than TPO may be essential for platelet production.
We now report that in the absence of TPO, induction of megakaryocyte motility with specific chemokines is sufficient to promote platelet production in TPO-/- and C-mpl-/- mice. We have identified chemokines, including Stromal-cell derived factor-1 (SDF-1) and Fibroblast growth factor-4 (FGF-4) that increased the number of platelets in TPO-/- and C-mpl-/- mice. We demonstrate that plasma elevation of these chemokines/cytokines restores platelet counts in the TPO-/- or TPO receptor C-mpl-/- mice. We also propose a novel mechanism whereby chemokines enhance platelet production. We show that chemokines by enhancing megakaryocyte motility promote the translocation of hematopoietic stem and progenitors from a non-permissive (osteoblastic region) to a permissive (Vascular region) environment augmenting maturation of megakaryocyte progenitors, therefore setting up the stage for platelet production. We recently reported chemokines/cytokines which can mobilize hematopoietic stem cells into the peripheral blood like G-CSF or SDF-1, induce activation of matrix metalloproteinases (MMPs), specifically MMP-9 in the bone marrow, which facilitate the release of soluble kit ligand (Cell Vol.109:625-637 2002; Nature Medicine June 2002). Here, we demonstrate that endothelial-derived chemokines/cytokines such as SDF-1 or FGF-4 can induce expression of the adhesion molecule very late antigen-4 (VLA-4). Inhibition of either MMP-9 or VLA-4 results in profound impairment in platelet production. These data suggest that the TPO/C-mpl pathway functions as a potent thrombopoietic amplifier, while expression of chemokine receptors on megakaryocytes are the decisive checkpoints that promote maturation and polyploidization of megakaryocytes and thrombopoiesis.
Keywords: Thrombopoietin\ SDF-1\ FGF-4 |
