Abstract
Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), plays a critical role in the pathogenesis of OSA-associated morbidities, especially in the cardiovascular and respiratory systems. Oxidative stress and inflammation induced by IH are suggested as main contributors of end-organ dysfunction in OSA patients and animal models. Since the molecular mechanisms underlying these in vivo pathological responses remain poorly understood, implementation of experimental in vitro cell-based systems capable of inducing high-frequency IH would be highly desirable. Here, we describe the design, fabrication, and validation of a versatile chip for subjecting cultured cells to fast changes in gas partial pressure and to cyclic stretch. The chip is fabricated with polydimethylsiloxane (PDMS) and consists of a cylindrical well-covered by a thin membrane. Cells cultured on top of the membrane can be subjected to fast changes in oxygen concentration (equilibrium time ~6 s). Moreover, cells can be subjected to cyclic stretch at cardiac or respiratory frequencies independently or simultaneously. Rat bone marrow-derived mesenchymal stem cells (MSCs) exposed to IH mimicking OSA and cyclic stretch at cardiac frequencies revealed that hypoxia-inducible factor 1α (HIF-1α) expression was increased in response to both stimuli. Thus, the chip provides a versatile tool for the study of cellular responses to cyclical hypoxia and stretch.
Highlights
Obstructive sleep apnea (OSA) is a highly prevalent disorder affecting 3–17% of the adult population (Peppard et al, 2013)
Even though hypoxia-inducible factor 1α (HIF-1α) induction was initially described in the context of cellular responses to reduced oxygen tension, its activation is not restricted to hypoxia (Dery et al, 2005; Kuschel et al, 2012)
We describe a low-cost and easy fabrication chip devised to investigate cellular responses to fast changes in gas composition typical of obstructive sleep apnea (OSA)
Summary
Obstructive sleep apnea (OSA) is a highly prevalent disorder affecting 3–17% of the adult population (Peppard et al, 2013). Most of the deleterious consequences of OSA, those affecting the cardiovascular system, are exacerbated by oxidative stress and inflammatory cascades associated with the activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway (Peng et al, 2006; Yuan et al, 2008; Belaidi et al, 2009; He et al, 2014). Biomechanical studies revealed that HIF-1α is upregulated in cells and tissues exposed to stretch (Kim et al, 2002; Milkiewicz et al, 2007; Lim et al, 2011), leading to similar cellular responses to those triggered by hypoxia (Milkiewicz et al, 2007; Leong et al, 2012) This is relevant since, in OSA, respiratory, and cardiovascular cells are subjected to concomitant IH and mechanical stretch. Published data support the notion that the hypoxic stimulus could mobilize mesenchymal stem cells (MSCs) and other progenitor cells from the bone marrow (Carreras et al, 2009; Rey et al, 2009; Gharib et al, 2010; Vertelov et al, 2013; Zan et al, 2015)
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