Neural stem/progenitor cell proliferation and differentiation are also regulated by ROS ( Le Belle et al., 2011, Prozorovski et al., 2008 and Smith et al.,

2000). Changes in stem cell function are involved in the adaptation to declining oxygen availability, such as those that occur with increasing altitude or cardiopulmonary disease. Neuron-like glomus cells in the carotid body mediate these responses by sensing oxygen levels in the blood and inducing hyperventilation during hypoxemia. Exposure of mice to hypoxia induces the proliferation of glia-like stem cells that remodel the carotid body in response to hypoxia to increase the number of glomus cells (Pardal et al., 2007). Hypoxia also learn more increases erythropoiesis by inducing erythropoietin expression in the kidney and liver (Semenza, 2009). Hypoxia increases the total number and proliferation of HSCs and multipotent progenitors (Li et al., 2011). It is possible that this involves indirect effects of hypoxia on cell death or cell turnover. Alternatively, because this website most HSCs localize close to blood vessels (Kiel et al., 2005 and Méndez-Ferrer et al., 2010), it is possible that their niche senses changes in oxygen levels. Because other stem cells, including some neural stem cells (Mirzadeh et al.,

2008 and Shen et al., 2008), also reside in perivascular microenvironments, it is conceivable that stem cells in multiple tissues are directly influenced by oxygen levels (Figure 4). Regardless of the mechanisms, multiple tissues are remodeled in response to hypoxia, partly due to changes in stem/progenitor cell function. It has been hypothesized that most stem cells reside in hypoxic niches that enable them to suppress oxidative damage by relying upon glycolysis rather than mitochondrial oxidative

phosphorylation (Mohyeldin et al., 2010, Parmar et al., 2007 and Simsek et al., 2010); however, this has not yet been tested in most tissues or in most developmental contexts. Hypoxic microenvironments may not protect stem cells from oxidative stress because hypoxia, paradoxically, can lead to the generation of elevated ROS levels (Brunelle et al., 2005 and Guzy and Schumacker, 2006). Nonetheless, evidence suggests that many bone marrow HSCs and at least some neural stem cells in adult mice reside in PD184352 (CI-1040) hypoxic environments. This may appear superficially inconsistent with the idea that HSCs often reside perivascularly; however, HSCs reside adjacent to sinusoidal blood vessels in hematopoietic tissues (Kiel et al., 2005). Sinusoids are a specialized form of vasculature found only in hematopoietic tissues. Sinusoids carry slow veinous circulation that is not designed to transport oxygen around the body as much as to provide specialized vasculature through which hematopoietic cells can intravasate into circulation. Thus, the perisinusoidal environment in the bone marrow may be relatively hypoxic. Stem cell maintenance also depends upon mechanisms that regulate adaptation to lower oxygen tensions.