Intermittent Hypoxia Mobilizes Bone Marrow-Derived Very Small Embryonic-Like Stem Cells and Activates Developmental Transcriptional Programs in Mice

OBSTRUCTIVE SLEEP APNEA (OSA) IS A PREVALENT DISORDER IN CHILDREN1 AND ADULTS2,3 AND IS CHARACTERIZED BY THE OCCURRENCE OF repetitive episodes of airflow obstruction during sleep, leading to intermittent hypoxia (IH) and reoxygenation.4 The morbid consequences of OSA are substantial and include cardiovascular, neurocognitive, and metabolic dysfunction.5–11 For example, patients with OSA exhibit substantial memory and executive functional losses, have increased circulating markers of oxidative stress and inflammation, and develop regional gray matter loss.12–14 In children, sleep apnea is associated with significant neurocognitive abnormalities, including attention deficits and poor school performance.15 Exposure to IH has now been widely used to model sleep apnea in animals,16,17 and, while such model does not mimic all aspects of OSA, it recapitulates many of the pathophysiologic sequelae of OSA in humans, such as increased oxidative stress, hypertension and endothelial dysfunction, insulin resistance, and cognitive deficits.18–22 To more closely approximate human OSA, we and others have developed mouse models in which exposure to IH is applied only during periods of sleep and removed upon either arousal or wakefulness.17,23–25 However, although recurrent hypoxia during sleep is a key characteristic of OSA, the molecular mechanisms by which IH promotes end-organ injury and, importantly, the responses mounted by the host to mitigate this effect remain poorly understood. Accumulating evidence suggests that pluripotent stem cells residing in the bone marrow (BM) play an important role in the homeostasis and turnover of peripheral tissues and can be mobilized from the BM into the circulation during tissue injury and stress.26–30 Recruitment of BM-derived stem-cell niches have been proposed as a major endogenous source for facilitation of structural and functional recovery, as well as promotion of the regeneration of damaged organs.31,32 Ratajczak et al.33 have recently identified a homogenous population of rare, small (∼3.7 μm) pluripotent stem cells residing in murine BM that express cellular markers characteristic for embryonic lineage and have shown that such stem cells can differentiate into lineage-committed cells from all 3 germ layers. Indeed, Sca-1+ Lin− CD45− very small embryonic-like stem cells (VSELs) can be mobilized from the BM to peripheral blood (PB) in response to specific chemokine gradients, including stromal cell–derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF).33,34 We have previously reported on the recruitment of VSELs from BM to PB following tissue-specific injury, including stroke30,35 and myocardial infarction.27,29 In the present study, we hypothesized that mice exposed to IH will increase plasma levels of stem cell–specific chemoattractants and mobilize BM-derived VSELs into the PB. Furthermore, since these pluripotent stem cells possess the ability to differentiate into any cell type, we performed gene expression profiling to systematically map the transcriptional architecture of activated programs within VSELs in response to IH.