scholarly journals Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1534-1543 ◽  
Author(s):  
Matilda Rehn ◽  
André Olsson ◽  
Kristian Reckzeh ◽  
Eva Diffner ◽  
Peter Carmeliet ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Stem Cell ◽  
Growth Factor ◽  
Hematopoietic Stem Cell ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Endothelial ◽  
Low Oxygen ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor

Abstract Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or up-regulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfaδ/δ, where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfaδ/δ mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-VEGFA axis.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4823-4823
Author(s):  
Matilda Rehn ◽  
Jorg Cammenga
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Stem Cell ◽  
Growth Factor ◽  
Conflicts Of Interest ◽  
Proper Function ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Hypoxic Induction ◽  
Endothelial Growth Factor ◽  
Fetal Erythropoiesis

Abstract 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 Vegfaδ/δ, where the HRE in the Vegfa promoter is deleted. Here we have investigated the role of hypoxic Vegfa in fetal hematopoiesis. The Vegfaδ/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 Vegfaδ/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 Vegfaδ/δ mice. Fetuses at day 15.5 are pale and have significantly lower amounts of Ter119+ CD71low 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. Disclosures: No relevant conflicts of interest to declare.

Hey2 acts upstream of Notch in hematopoietic stem cell specification in zebrafish embryos

Blood ◽  
2010 ◽  
Vol 116 (12) ◽  
pp. 2046-2056 ◽  
Author(s):  
Jonathan M. Rowlinson ◽  
Martin Gering
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Transcription Factor ◽  
Stem Cell ◽  
Growth Factor ◽  
Notch Signaling ◽  
Dorsal Aorta ◽  
Zebrafish Embryos ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor

Abstract Hematopoietic stem cells (HSCs) are essential for homeostasis and injury-induced regeneration of the vertebrate blood system. Although HSC transplantations constitute the most common type of stem cell therapy applied in the clinic, we know relatively little about the molecular programming of HSCs during vertebrate embryogenesis. In vertebrate embryos, HSCs form in close association with the ventral wall of the dorsal aorta. We have shown previously that in zebrafish, HSC formation depends on the presence of a signaling cascade that involves Hedgehog, vascular endothelial growth factor, and Notch signaling. Here, we reveal that Hey2, a hairy/enhancer-of-split–related basic helix-loop-helix transcription factor often believed to act downstream of Notch, is also required for HSC formation. In dorsal aorta progenitors, Hey2 expression is induced downstream of cloche and the transcription factor Scl/Tal1, and is maintained by Hedgehog and vascular endothelial growth factor signaling. Whereas knockdown of Hey2 expression results in a loss of Notch receptor expression in dorsal aorta angioblasts, activation of Notch signaling in hey2 morphants rescues HSC formation in zebrafish embryos. These results establish an essential role for Hey2 upstream of Notch in HSC formation.

scholarly journals Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1α

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4258-4263 ◽  
Author(s):  
Keita Kirito ◽  
Norma Fox ◽  
Norio Komatsu ◽  
Kenneth Kaushansky
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Stem Cell ◽  
Growth Factor ◽  
Hematopoietic Cells ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor ◽  
Marrow Cells

Abstract Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is also an important, nonredundant 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, hypoxia-inducible factor 1α (HIF-1α), by enhancing its protein stability. Moreover, VEGF expression is important for the TPO effect on primitive hematopoietic cells because blockade of the VEGF receptor with a specific inhibitor substantially blunts 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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