Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis

The role of the chemokine binding stromal-derived factor 1 (SDF-1) in norma l human megakaryopoiesis at the cellular and molecular levels and its compa rison with that of thrombopoietin (TPO) have not been determined. In this s tudy it was found that SDF-1, unlike TPO, does not stimulate alpha (IIb)bet a (+)(3) cell proliferation or differentiation or have an antiapoptotic eff ect. However, it does induce chemotaxis, trans-Matrigel migration, and secr etion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO Increase the adhesion of alpha (IIb)beta (+)(3) cells to fibrinogen and vitronectin. Investigati ng the intracellular signaling pathways induced by SDF-1 and TPO revealed s ome overlapping patterns of protein phosphorylation/activation (mitogen-act ivated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-ka ppaB). It was also found that though inhibition of phosphatidyl-inositol 3- kinase (PI-3K) by LY294002 in alpha (IIb)beta (+)(3) cells induced apoptosi s and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, th e inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on t he survival, proliferation, and migration of these cells. Hence, it is sugg ested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K-AKT axis is differenti ally involved in TPO- and SDF-1-dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1-regulated adhesion to fibrinogen and vitronectin, and SDF-1-mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal huma n megakaryopoiesis and indicates the molecular basis of the observed differ ences in cellular responses. (C) 2000 by The American Society of Hematology .