In-Vitro Studies Of Recombinant Human Platelet Factor-4 - Inhibition Of Megakaryocytopoiesis And Angiogenesis

초록

We have previously shown that platelet factor 4 (PF4), a platelet-specific CXC chemokine, can directly and specifically inhibit human megakaryocyte colony formation, and we therefore hypothesized that PF4 might function as a negative autocrine regulator for megakaryocytopoiesis. Because of the high PF4 concentration needed to observe this effect, there was a concern that contaminating protein in the PF4 preparation might be inhibiting megakaryocyte development or that the phenomenon represents a non-specific effect resulted from high levels of PF4 on the megakaryocyte precursors. We have now corroborated our initial studies by showing that recombinant human (rH) PF4, like the native protein, inhibited megakaryocytopoiesis and proliferation of the human umbilical vein endothelial cells (HUVECs), making it unlikely that the effect is secondary to a contaminant. Simialr results were seen with CD34(+) purified marrow cells. These results suggest that PF4 do not inhibit megakaryocytopoiesis non-specifically, but possibly interact with chemokine receptors on the megakaryocyte precursors and HUVECs as much as they do with IL-8 receptor alpha and beta on neutrophils. Based on these results, we propose a hypothesis that megakaryocyte differentiation is regulated in the marrow microenvironment by one or more chemokines.

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