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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2504-2512.
Prepublished online as a Blood First Edition Paper on December 4, 2003; DOI 10.1182/blood-2003-07-2563.
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HEMATOPOIESIS
VEGF-A165 augments erythropoietic development from human embryonic stem cells
Chantal Cerdan,
Anne Rouleau, and
Mickie Bhatia
From the Robarts Research Institute, Stem Cell Biology and Regenerative Medicine, and the Departments of Microbiology and Immunology and Physiology, The University of Western Ontario, London, ON, Canada.
Combinations of hematopoietic cytokines and the ventral mesoderm inducer BMP-4 have recently been shown to augment hematopoietic cell fate of human embryonic stem cells (hESCs) during embryoid body (EB) development. However, factors capable of regulating lineage commitment of hESC-derived hematopoiesis have yet to be reported. Here we show that vascular endothelial growth factor (VEGF-A165) selectively promotes erythropoietic development from hESCs. Effects of VEGF-A165 were dependent on the presence of hematopoietic cytokines and BMP-4, and could be augmented by addition of erythropoietin (EPO). Treatment of human EBs with VEGF-A165 increased the frequency of cells coexpressing CD34 and the VEGF-A165 receptor KDR, as well as cells expressing erythroid markers. Although fetal/adult globins were unaffected, VEGF-A165 induced the expression of embryonic zeta ( ) and epsilon ( ) globins, and was accompanied by expression of the hematopoietic transcription factor SCL/Tal-1. In addition to promoting erythropoietic differentiation from hESCs, the presence of VEGF-A165 enhanced the in vitro self-renewal potential of primitive hematopoietic cells capable of erythroid progenitor capacity. Our study demonstrates a role for VEGF-A165 during erythropoiesis of differentiating hESCs, thereby providing the first evidence for a factor capable of regulating hematopoietic lineage development of hESCs.
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