HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo

Abstract

Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC) function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α), a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver), and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO) approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPC) are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPC and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages.

The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability

“…A recent study also observed hypoxia in the FL, 15 and ours is the first description of a role for HIF signaling in the survival of FL HSCs. Given the previously described role for hypoxia in yolk sac, 16 AGM, 18 and BM HSCs, 21 we propose that hypoxia-and O 2 -sensitive factors represent universal regulators of hematopoietic progenitor cells.…”

“…5,6,15 Embryoid bodies generated in vitro from Arntdeficient mouse embryonic stem cells form fewer hematopoietic colonies, suggesting that hypoxia promotes formation of early hematopoietic cells. 16,17 Consistently, germline Arnt deletion results in diminished numbers of yolk sac hematopoietic progenitors, demonstrating that HIF is critical for hematopoietic development.…”

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

“…In spite of the hyper-vascularity of the bone marrow cavity, the oxygen tension is as low as in venous blood, owing to high levels of oxygen consumption by the proliferating HSPCs (Nombela-Arrieta, Pivarnik et al 2013). Conditional knock-out of the Hif1α gene leads to increased levels of reactive oxygen species (ROS) in HSPCs and depletion of the cells, which suggests that HIF1α is indispensable for stem cell function in the hematopoietic system (Imanirad, Solaimani Kartalaei et al 2014). In addition, studies have shown that HSPCs are generally quiescent cells that are sensitive to intracellular ROS (Orkin and Zon 2008).…”

Harnessing developmental processes for vascular engineering and regeneration

“…Other physicochemical parameters include proteolytic matrix remodeling and matrix stiffness, which affect vascular morphogenesis and network formation Busnadiego et al, 2013;Turturro et al, 2013). Oxygen availability has also been shown to play a crucial role in early vascular development (Imanirad et al, 2014). This range of physicochemical properties that regulate vascular development in vivo represents the many variables that must be considered for vascular engineering and regeneration approaches.…”