For more than two billion years on this planet, O2 has been the go-to gas for generating efficient cellular energy. But life on Earth never takes oxygen for granted. “When it runs low, cells swiftly adapt,” says cell biologist Celeste Simon.
This ancient adaptive reaction, known as the low-oxygen, or hypoxia, response, typically involves a cascade of protective changes in cells: protein synthesis drops and cells switch to a less efficient process of energy production that doesn’t require oxygen. But organisms have evolved uses for the hypoxia response that are not merely protective.
Simon, an HHMI investigator at the University of Pennsylvania, recently found evidence that the response is crucial for maintaining the health of stem cells in the hippocampus, a key memory region of the brain. The discovery could alter our understanding of a host of stem cell-related brain conditions.
“It’s a seemingly puzzling finding, but the normal functioning of neural stem cells in the hippocampus does appear to require low oxygen levels and consequent hypoxia responses,” says Simon.
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The neural stem cells in question are meant to keep the population of hippocampal neurons replenished. A certain level of this replenishment, or “neurogenesis,” is increasingly thought to be important for a healthy mood and memory. Interruption of neurogenesis causes depression-like behavior in mice, while in humans antidepressant medications appear to work largely by boosting neurogenesis. Alzheimer’s disease, as well as ordinary aging, features a decline in this replenishment process.
In an October 2010 Nature Cell Biology paper, Simon and her colleagues reported that neurogenesis markedly declined in mice when their brain cells were genetically altered to knock out their ability to produce the hypoxia response. “We saw fewer stem cells, fewer of the immature daughter cells that stem cells produce, and fewer connections coming from these daughter cells,” says Simon.
Why would the hypoxia response even matter to brain cells, which are known for their voracious intake of oxygen? Simon and her team found that the usual habitat for stem cells in the mouse hippocampus is riddled with low-oxygen zones, where the signs of stem cell activity are particularly evident. “It seems that these lower-oxygen zones are essential for maintaining neural stem cells’ healthy activity,” she says. “In fact, these stem cells appear to be spread out, in and near these zones, with different activities depending on the oxygen level, suggesting that the stem cells’ activities are being regulated by the local oxygen levels.” The hypoxia response may be acting as a growth signal for the stem cells.
Preliminary tests on the engineered no-hypoxia-response mice suggest that they do have behavioral defects consistent with those seen in other mouse models of depression. Simon and her colleagues now are trying to determine whether inadequate hypoxia responses in the hippocampus might be at least partly to blame for depression in humans.
Some activities are known to promote neurogenesis—such as physical exercise—and here again Simon wants to know whether hypoxia signaling is a factor. “One of the things on our to-do list is to determine how exercise affects oxygen distribution in these stem-cell-rich regions of the hippocampus,” she says.
The clinical possibilities don’t end there, given the links between decreased neurogenesis and both Alzheimer’s and aging. “We haven’t yet had a chance to investigate in this area, but naturally we’re intrigued by the possibility that age-related declines in the hypoxia response help to drive the age-related functional declines we see in the brain and other organs,” says Simon.
It might seem odd that a protective response to low oxygen has ended up being adopted by some cells so that they actually need a bit of hypoxia to function normally. But most of Simon’s prior research in the field has aimed at understanding such adaptations. “Embryonic cells, for example, can grow so quickly that they create a hypoxic zone around themselves,” she says. “This switches on their hypoxia response, which among other things promotes the sprouting of new blood vessels toward them, so that they can continue to grow.” Her work has helped to show, too, how the hypoxia response is used in some cancer cells and also directly regulates stem cells in the developing bone marrow and heart.
“It’s been clear for some time now that hypoxia signaling is relevant in many areas of biology,” she says. “But it could turn out to have more importance for health and disease than we’d ever imagined.”