Thrombopoietin stimulates vascular endothelial cell growth factor (VEGF) production in hematopoietic stem cells

Thrombopoietin (TPO) is a pivotal and nonredundant hematopoietic cytokine, supporting the survival, self-renewal activity and proliferation of hematopoietic stem and progenitor cells, the growth and differentiation of megakaryocytes, and the functional activation of their progeny, blood platelets. TPO exerts these effects through regulating the abundance or subcellular localization of several transcription factors, including the homeodomain proteins HOXB4 and HOXA9. In addition to these effects, TPO helps orchestrate a cytokine-network in the bone marrow microenvironment that supports hematopoietic stem cell (HSC) function. In recent studies we have shown that TPO stimulates production of vascular endothelial cell growth factor (VEGF), another cytokine vital for HSC physiology, promoting their survival and expansion into committed hematopoietic progenitors. Like several other effects of the cytokine, the effect of TPO on VEGF expression is mediated by stabilization and activation of the primary transcription factor responsible for VEGF expression, the oxygen tension responsive hypoxia inducible factor-1 (HIF-1). Together with the observation that bone marrow microenvironment is hypoxic and hypoxia simulates the repopulating activity of HSCs, our observations suggest that TPO mimics hypoxia and controls important genes required for HSC cycling, including VEGF, adding to our understanding of how the hormone contributes to HSC function.