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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4258-4263.
Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2004-07-2712.
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Submitted July 20, 2004
Accepted December 28, 2004
Thrombopoietin enhances expression of Vascular Endothelial Growth Factor (VEGF) in primitive hematopoietic cells through HIF-1
Keita Kirito, Norma Fox, Norio Komatsu, and Kenneth Kaushansky*
Department of Medicine, University of California, San Diego, San Diego, CA, USA
Department of Hematology, University of Yamanashi, Kofu, Yamanashi, Japan
* Corresponding author; email: kkaushansky{at}ucsd.edu.
Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is also an important, non-redundant 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, HIF-1 , by enhancing its stability. Moreover, VEGF expression was important for the TPO effect on primitive hematopoietic cells, as blockade of the VEGF receptor with a specific inhibitor substantially blunted 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.
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