Hypoxic induction of vascular endothelial growth factor regulates erythropoiesis but not hematopoietic stem cell function in the fetal liver

Abstract

Hypoxia is an important factor in the hematopoietic stem cell (HSC) niche in the bone marrow (BM) but whether it also plays a role in the regulation of fetal liver (FL) HSCs is unclear. Definitive HSCs first arise in the AGM region and the placenta during development and later migrate to the fetal liver (FL). FL HSCs undergo extensive proliferation in the liver and migrate to the bone marrow (BM) shortly before birth, where they become quiescent. The molecular mechanisms behind this switch in proliferation remain elusive. While many components of the BM stem cell niche have been identified, relatively little is known about the FL HSC niche. Vascular endothelial growth factor A (VEGFA) is essential for adult HSC survival and hypoxic induction of Vegfa in adult HSC is required for proper function. Mice with defective hypoxia-induced Vegfa expression (Vegfaδ/δ) show a partial embryonic lethality and increases the numbers of phenotypically defined hematopoietic stem and progenitor cells in the FL, but whether stem cell function is affected in FL HSCs has not been examined. To investigate whether hypoxia-induced Vegfa is involved in regulation of fetal HSC function and to identify the reason for the embryonic lethality we have examined FL hematopoiesis in the Vegfaδ/δ model. We show that fetal erythropoiesis is severely impaired when hypoxic induction of Vegfa is lacking. FL HSCs deficient for hypoxia-induced Vegfa expression have normal HSC function arguing against a hypoxic FL HSC niche. However, after adaptation of FL HSCs to the BM microenvironment, FL HSCs lose their function as measured by serial transplantation. Hypoxia is an important factor in the hematopoietic stem cell (HSC) niche in the bone marrow (BM) but whether it also plays a role in the regulation of fetal liver (FL) HSCs is unclear. Definitive HSCs first arise in the AGM region and the placenta during development and later migrate to the fetal liver (FL). FL HSCs undergo extensive proliferation in the liver and migrate to the bone marrow (BM) shortly before birth, where they become quiescent. The molecular mechanisms behind this switch in proliferation remain elusive. While many components of the BM stem cell niche have been identified, relatively little is known about the FL HSC niche. Vascular endothelial growth factor A (VEGFA) is essential for adult HSC survival and hypoxic induction of Vegfa in adult HSC is required for proper function. Mice with defective hypoxia-induced Vegfa expression (Vegfaδ/δ) show a partial embryonic lethality and increases the numbers of phenotypically defined hematopoietic stem and progenitor cells in the FL, but whether stem cell function is affected in FL HSCs has not been examined. To investigate whether hypoxia-induced Vegfa is involved in regulation of fetal HSC function and to identify the reason for the embryonic lethality we have examined FL hematopoiesis in the Vegfaδ/δ model. We show that fetal erythropoiesis is severely impaired when hypoxic induction of Vegfa is lacking. FL HSCs deficient for hypoxia-induced Vegfa expression have normal HSC function arguing against a hypoxic FL HSC niche. However, after adaptation of FL HSCs to the BM microenvironment, FL HSCs lose their function as measured by serial transplantation.