Control of tissue regeneration through oxygen concentrations

For centuries oxygen has been thought to be the key to all life. Without it, eukaryotic organisms including cells cannot survive. Oxidative stress, reactive oxygen and antioxidants have become household terms, yet it has only been recently that researchers have started to unravel the essential complex regulatory role oxygen plays in stem cell maintenance, proliferation, migration, and engraftment for tissue regeneration. Both adult and embryonic stem cells have now been shown to be housed in "niches" which possess 1-5% oxygen levels, considerably lower than 21% ambient oxygen. The term hypoxia is used to describe these lower oxygen levels but recent critics suggest this may be more accurately described as normoxia. Much evidence has come to light that cells possess several key factors that function as oxygen sensors and that oxygen status within target tissues may play a key role in stem cell engraftment and differentiation during tissue repair. One of the key factors involved is hypoxia inducible factor (HIF). This factor can both enhance cellular differentiation, as well as rapidly change local oxygen levels through stimulation of angiogenesis and reduction of cellular oxygen requirements, by switching the cell from aerobic to anaerobic respiration. Thus during tissue injury, hypoxic areas within the damaged region can induce expression of factors essential for the recruitment and engraftment of stem cells for regeneration. Further, stem cells when exposed to higher oxygen in the blood stream during mobilization, switch from anaerobic respiration in their hypoxic niche, to aerobic metabolism during proliferation. During this period of high energy production and cellular proliferation, reactive oxygen is generated, which in concert with other factors alters gene expression towards terminal differentiation. Thus oxygen tension may be an essential component for the regeneration of tissue.