Six years ago, researchers at Stanford connected the bloodstreams of old and young lab mice, and observed that the livers of the old mice quickly recovered a youthful capacity to heal themselves after damage. The researchers concluded that an unknown factor or factors from the young mice’s blood had had a rejuvenating effect on the stem cells and related “progenitor” cells in the livers of the old mice.
Just as dramatically, researchers at University College London reported on June 8 that a molecule called thymosin β4 can induce progenitor cells in the hearts of mice to repair heart-attack damage by producing new cardiomyocytes—mature heart cells.
These and other experiments demonstrate not only the promise of therapies based on stem and progenitor cells, but also the importance of providing these cells with the proper signaling environment, or “niche.” This may be especially true for stem and progenitor cells in the brain.
“Being able to mimic the physiologic environment of neural and other stem cells is going to be crucial in developing therapies,” says Celeste Simon, a cell biologist and stem cell researcher at the University of Pennsylvania.
Where neurogenesis happens
Stem cells in tissues normally stay in a relatively inactive state, occasionally dividing to maintain their own population or to produce a background supply of progenitor cells. The latter are intermediate cells that go on to produce the mature, “differentiated” cells that make up working tissue. When an injury occurs nearby, stem cells move into a more active state, and are more likely to give birth to fast-expanding populations of progenitor cells.
The same stem cell dynamics are seen in the nervous system, but evolution appears to have left the adult brain—especially in mammals—with less natural regenerative capacity than other tissues possess. Scientists believe that this lack of regenerative capacity is mean to protect the specialized and more or less permanent circuitry of the developed brain. So far, only two zones in mammals’ brains are known to replenish lost neurons during adult life. One is the subventricular zone (SVZ), which supplies new neurons and other types of brain cell to the olfactory bulb, the striatum and cortical areas. The other is the subgranular zone (SGZ) of the hippocampus—a key area for the storage and recall of memories concerning places and experiences.
The SGZ gets plenty of scientific attention because the production of new neurons (“neurogenesis”) there seems important for maintaining normal memory and mood, and is lowered by a host of common factors including normal aging, Alzheimer’s disease, chronic stress, and lack of physical exercise.
Research in this area is still in its early stages, but is advancing rapidly. On June 9, for example, researchers led by Columbia University neuroscientist Rene Hen reported in Neuron on a study of how life experience affects the behavior of SGZ stem cells in mice. Using new and powerful techniques for tracing stem cells and their successor progenitor cells, the researchers found unexpectedly that the stress-induced decrease in SGZ neurogenesis is accompanied by an increase in the numbers of SGZ stem cells.
In other words, under adverse conditions the “fate” of each such neural stem cell is more likely to be a new neural stem cell, rather than a progenitor and then a neuron. “In an impoverished environment, instead of producing more neurons the stem cells produce more stem cells,” says Hen. “So this suggests that in stressful conditions it may be advantageous for the brain produce a reserve of stem cells that can then be used [to provide a surge of new neurons] when the environment becomes more favorable.”
In turn, this hints that neurogenesis occurs near the olfactory bulb and the hippocampus because these regions especially require flexibility in fast-changing circumstances. But could scientists boost or restore this flexibility to help repair a damaged brain?
Looking for stem cells’ control switches
The recipes for boosting neurogenesis are still incomplete. “A lot of work has dealt with the role of growth factors such as BDNF and VEGF,” says Hen. “But which growth factor is going to favor, for example, the stem cell fate over the neuronal fate, is not yet known.”
Another important factor appears to be oxygen—or the lack of it. In recent years, several groups including Simon’s have found that stem cells in various tissues, including the SGZ, appear to require low-oxygen zones for normal functioning. In a paper late last year, Simon’s team linked stem cell activity in the SGZ to regions with particularly low oxygen levels, and found that the deletion of a key low-oxygen-indicator molecule, Hif-1α, seriously impairs local stem cells’ abilities to proliferate and produce mature neurons. More recently she has found evidence that when the antidepressant lithium boosts SGZ neurogenesis in mice, it does so via Hif-1α. Thus, locally boosting this molecule or other elements in its signaling pathway could be a strategy of interest for drug developers.
Why stem cells in the SGZ and other tissues require low oxygen—and also, as Simon notes, low nutrient levels—remains a puzzle. On the one hand, a low-oxygen, low-nutrient environment may keep stem cells in a state of suspended animation. “We would argue that this particular state is conducive to a longer lifespan and a high level of genomic integrity,” she says. But what is it that makes these SGZ stem cells break out of this quiet state and move into high-gear neurogenesis? And why is it that some stem cell populations, including SVZ stem cells, don’t seem to need a low-oxygen niche?
Answering those questions is probably going to require years more work, says Simon. “To take the next experimental steps, we need to create more transgenic mice, which we’re in the process of doing, but it takes a while to generate those new mouse lines.”
Neural stem and progenitor cells may carry some of their niche with them. A team of researchers at Stanford reported this January that human neural stem cells, injected into rat brains after a stroke, markedly improved the recovery process, in part by secreting growth factors such as VEGF. “The [cells] enhanced new blood vessel formation and also reduced the inflammatory response after a stroke,” says Tonya Bliss, a stem cell researcher at Stanford who was one of the senior authors of the study.
Inflammation appears to be one of the major factors affecting neural stem cell niches. In May, researchers led by senior author Samia Khoury, a neurologist at Harvard Medical School, reported that the chronic activation of brain immune cells known as microglial cells erodes the brain’s ability to repair damaged nerve fibers in a mouse model of multiple sclerosis (MS). When Khoury’s team gave the mice the drug minocycline, to reduce microglial activation, they saw a sharp rise in the SVZ production of progenitor cells and oligodendrocytes—cells that maintain the myelin sheaths on nerve fibers—and a reduction of the usual MS-like damage.
These results could lead to the use of minocycline to improve the brain’s stem-cell-based self-repair capacity in chronic, progressive forms of MS. But Khoury’s work also highlights a big difference, for the stem cell niche, between acute and chronic microglial activation. “Acutely activated microglia secrete factors that are supportive of the stem cell niche, whereas chronically activated microglia do not,” she says. “So we think that this might explain why, in the chronic phase of MS, you see a decrease in the response of the stem cell niche to brain injury.”
It also might explain some of the weakness of the brain in other diseases involving long-term microglial activation, such as Alzheimer’s and Parkinson’s, she adds. “I think this is relevant to a lot of neurologic diseases.”