Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1α

Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is also an important, nonredundant mediator of hematopoietic stem cell (HSC) development. For example, following transplantation, HSC expansion is approximately 15-fold more robust in normal than in Tpo(-/-) mice. Vascular endothelial growth factor (VEGF) also plays an important role in HSC development, where it acts in an intracellular autocrine fashion to promote cell survival. Thus, we tested the hypothesis that TPO affects the autocrine production of VEGF to account for its favorable effects on HSCs. We found that VEGF transcripts are reduced in purified sca-1(+)/c-kit(+)/Gr-1(-) marrow cells derived from Tpo(-/-) mice and that TPO induces VEGF transcripts in these primitive hematopoietic cells. Additional studies determined that TPO induces VEGF expression by increasing the level of its primary transcription factor, hypoxia-inducible factor 1alpha (HIF-1alpha), by enhancing its protein stability. Moreover, VEGF expression is important for the TPO effect on primitive hematopoietic cells because blockade of the VEGF receptor with a specific inhibitor substantially blunts TPO-induced growth of single sca-1(+)/c-kit(+)/Gr-1(-) marrow cells in serum-free cultures. Along with previous findings that TPO affects Hox transcription factors that regulate HSC proliferation, these data contribute to our growing understanding of the mechanisms by which a hormone can influence stem cell development.