Magnitude and Duration of Hypoxia Direct Intestinal Stem Cell Function

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

ABSTRACT Ischemia injury in the small intestine is initiated by an occlusion to underlying microvasculature that rapidly decreases oxygen levels, causing pathophysiologic hypoxia at the epithelium. Critical damage to intestinal epithelial cells can cause loss of barrier function from weakened or dying cells, exposing the rest of the body to bacteria and hazardous luminal contents. Although the impact of ischemia on differentiated intestinal endothelium has been studied extensively, the impact of hypoxia on the human intestinal epithelial stem cells (ISC), and the repair mechanisms responsible for the switch from reversible to irreversible epithelial damage remain to be discovered. Hypoxia can reduce epithelial cell viability, compromise epithelial membrane integrity, and alter the cellular composition of the epithelium. At the cellular level, hypoxia triggers the master transcriptional factor hypoxia-inducible-factor-1 (HIF-1) to stabilize and translocate to the nucleus, where it reprograms genes to regulate epithelial cell fate. While hypoxia and subsequent effects of HIF-1? are known to impart a number of protective phenotypes in differentiated epithelial cells or colon cancer cell lines, the impact of the hypoxia magnitude and duration on the self-renewal and differentiation capacity of ISCs has not been studied. Other types of stem cells exhibit increased proliferation and pluripotency following hypoxic conditioning. These findings suggest that the magnitude (% oxygen available) and duration (short-term vs. long-term) of ischemic injury influences epithelial recovery--a recovery which is guided by ISCs. Therefore, I hypothesize during ischemic injury the loss of ISC stemness depends on the magnitude and duration of oxygen deprivation in a HIF-1 dependent manner. To test this hypothesis, I will 1) define how the magnitude and duration of hypoxia affect human ISC function in a 3D microphysiological model of the human intestinal epithelium, and 2) determine the role of HIF-1? in human ISC response to hypoxia. Identifying how HIF-1? impacts the self-renewal and differentiation capacities of human ISCs during hypoxia will accelerate development of novel strategies to spare the ISC compartment following hypoxic injury.