The role of platelet alpha-granular proteins in the regulation of thrombopoietin messenger RNA expression in human bone marrow stromal cells

Thrombopoietin (TPO), the specific cytokine that regulates platelet product ion, is expressed in human bone marrow (BM), kidney, and liver. There appea rs to be no regulation of TPO in the kidney and liver, but TPO messenger RN A (mRNA) expression can be modulated in the stromal cells of the BM. In thi s study, we used primary human BM stromal cells as a model to study the reg ulation of TPO mRNA expression in response to various platelet alpha-granul ar proteins. We showed that platelet-derived growth factor (PDGF) BE and fi broblast growth factor (FGF) 2 stimulated TPO mRNA expression in both a dos e-dependent and time-dependent manner. The addition of 50 ng/mL of PDGF and 20 ng/mL of FGF resulted in maximal induction of TPO mRNA expression in 4 hours. We also found that platelet factor 4 (PF4), thrombospondin (TSP), an d transforming growth factor-beta (TGF-beta) are negative modulators of meg akaryocytopoiesis. We observed suppression in TPO mRNA expression with 1 mu g/mL of both PF4 and TSP and 50 ng/mL of TGF-beta, with maximal suppressio n occurring 4 hours after the addition of these proteins. Finally, the addi tion of whole-platelet lysate produced a dose-dependent inhibition of TPO e xpression. On the basis of these findings, we propose that the platelet alp ha-granular proteins studied may regulate TPO gene expression in BM stromal cells by means of a feedback mechanism. (C) 2000 by The American Society o f Hematology.