Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche  Ahmed Mohyeldin, Tomás Garzón-Muvdi, Alfredo Quiñones-Hinojosa  Cell Stem Cell  Volume 7, Issue 2, Pages 150-161 (August 2010) DOI: 10.1016/j.stem.2010.07.007 Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 1 Low Oxygen Tension Measurements in Various Stem Cell Compartments Schematic models are depicted based on current available data for the hematopoietic, mesenchymal, and neural stem cells in their designated niches: the bone marrow, adipose tissue, and the subventricular zone (SVZ), respectively. Red cells represent HSCs, MSCs, and NSCs. Various oxygen tension measurements from the tissues and blood supply where hematopoietic and mesenchymal stem cells reside have been reported in the literature. Citations include data from direct measurements, mathematical models, or reviews written about the subject. Concentrations from both rodent and human data were used when it was available. Although direct measurements from the SVZ have never been performed, measurements of oxygen tension as low as 0.55% O2 in various areas of the brain suggest that gradients of oxygen may exist in the SVZ. Depiction of the SVZ niche and vascular supply are based on rodent data and are being used conceptually in this figure as characterization of the human SVZ and its relationship with local vasculature are a subject of ongoing research. Cell Stem Cell 2010 7, 150-161DOI: (10.1016/j.stem.2010.07.007) Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 2 Cancer Stem Cell Niche Nestin- and Notch-expressing glioma-initiating cells (cancer stem cells) were initially described to reside in a perivascular niche around tumor vasculature. Recent evidence suggests that NO produced by endothelial cells maintains the cancer stem cell phenotype. Inhibition of this signaling pathway results in loss of neurosphere forming capacity and attenuation of tumorigenic forming capacity in vivo. A secondary niche more distal from the vasculature exhibits lower oxygen tension and has also been shown to regulate the cancer stem cell phenotype. Adjacent to the rim of necrotic cells, this hypoxic niche contains cancer stem cells whose activity is modulated by multiple HIF-regulated genes, such as HIF-2α and HIF-1α, and other signaling molecules (Oct4, VEGF, Notch, and c-myc). Recent evidence suggests that cancer stem cells differentially respond to hypoxia with distinct HIF induction patterns. Targeted inhibition of HIF-2α inhibits self-renewal, proliferation, and survival in vitro and attenuates tumor initiation potential. Cell Stem Cell 2010 7, 150-161DOI: (10.1016/j.stem.2010.07.007) Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 3 Role of Oxygen in the Maintenance of Stemness in the Neural Stem Cell, Cancer Stem Cell, and Induced Pluripotent Stem Cell (A) At low oxygen tensions, HIF-1α is stabilized and dimerizes with HIF-1β to then translocate to the nucleus and act as transcriptional activators of a diverse array of genes, some of which are important for the maintenance of the pool of NSCs, such as cell-cycle regulators. HIF-1α and HIF-β complex is also able to inhibit phosphorylation of p53, inhibiting its activity in cell-cycle arrest and apoptosis. Low oxygen tensions also promote phosphorylation of JNK, which upregulates cyclin D1, which is involved in cell-cycle progression and self-renewal of NSCs. Also, the HIF complex modulates the activity of Notch signaling, through interaction with the notch intracellular domain (NICD) and precluding differentiation of NSCs. Further, upon ischemic insults to other parts in the brain, NSCs are exposed to humoral factors, such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which increase NSC proliferation. In particular, EPO increases NSC proliferation through activation of NF-κB signaling and directs NSC fate by upregulating the expression of the transcription factor Mash1. (B) In cancer stem cells (CSCs), HIF1α interacts with the NICD and modulates epithelial-to-mesenchymal transition (EMT) in addition to upregulating glycolitic genes and promoting angiogenesis. On the other hand, stabilization of HIF-2α increases the expression of important genes in the maintenance of a stem cell state, such as Oct4, and also increases the expression of master transcriptional regulator c-Myc in CSCs. (C) Hypoxia also has shown to play an important role in the generation of induced pluripotent stem cells (iPSCs), where stabilization of HIF-2α and/or HIF-3α may increase endogenous expression of transcription factors used to generate iPSCs from differentiated somatic cells, such as Oct4. It has been shown that knockdown of HIF-2α or HIF-3α, but not HIF-1α, leads to a decrease in the expression of Oct4, NANOG, and SOX2, important stem cell markers. Cell Stem Cell 2010 7, 150-161DOI: (10.1016/j.stem.2010.07.007) Copyright © 2010 Elsevier Inc. Terms and Conditions