Hypoxic Induction of Vascular Endothelial Growth Factor Regulates Fetal Erythropoiesis but Not Stem Cell Function

Abstract 4823

It has recently become apparent that hypoxia is an important factor in the hematopoietic stem cell (HSC) niche in the bone marrow (BM) but whether hypoxic niches also plays a role in regulation of fetal liver (FL) HSCs is not clear. Vascular endothelial growth factor A (VEGFA) is a key molecule in angiogenesis but is also known to be essential for adult HSC survival, mediated by a cell-intrinsic, autocrine mechanism. Vegfa expression can be induced by hypoxia-inducible factors (HIF), transcription factors that are stabilized in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). We have previously shown that hypoxic induction of Vegfa in adult HSCs is needed for proper function, using the mouse model Vegfa^δ/δ, where the HRE in the Vegfa promoter is deleted. Here we have investigated the role of hypoxic Vegfa in fetal hematopoiesis. The Vegfa^δ/δ genotype is partly embryonic lethal and we established that the major part of lethality in utero takes place between day 15.5 of development and birth. However, the exact reason for the lethality is not known. We speculated that the function of FL HSC might be reduced, and therefore BM seeding is inefficient and a cause of prenatal deaths. In contrary to our hypothesis, we now show that HSCs from Vegfa^δ/δ FL have a normal capacity to competitively repopulate adult recipients. On the other hand, fetal erythropoiesis is severely impaired in absence of hypoxia-induced Vegfa, possibly explaining the embryonic lethality of Vegfa^δ/δ mice. Fetuses at day 15.5 are pale and have significantly lower amounts of Ter119⁺ CD71^low erythrocytes in the FL compared to wild type controls. Our findings indicate that hypoxic regulation of Vegfa expression is important in fetal erythropoiesis, suggesting that hypoxic areas exist within the FL. However, HSCs are affected by such hypoxic areas only to a small extent and hypoxic Vegfa expression is not highly important in FL HSCs.