Support for the Brain—Import Stem Cells, or Pamper Your Own
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It is a lot to ask of transplanted neuronal stem cells to morph into functional neurons and insinuate themselves in exactly the right place to rebuild broken brain circuitry. However, the bar for therapeutic efficacy may not be so high. A study from Evan Snyder from the Burnham Institute, La Jolla, California, and Frances Platt of the University of Oxford, United Kingdom, published online March 11 in Nature Medicine, shows that for mice suffering from a metabolic neurodegenerative condition, transplanted stem cells do not need to replace, but instead can rescue at-risk neurons to prevent neurodegeneration. In their model, human stem cells, either from fetal brain or differentiated from ES cell lines in culture, worked just as well as mouse cells, with no sign of immune rejection.
In other stem cell news, a paper from Daniel Peterson and colleagues and another from Scott Small and colleagues chart the ups and downs of endogenous stem cells. They show that for neurogenesis, as for many physiological functions, there is a familiar pattern: stress bad, exercise good. The first study shows how acute stress reduces neurogenesis in the hippocampus of adult rats, while the second describes how exercise increases MRI signals that track neurogenesis in the dentate gyrus in humans.
Snyder and colleagues probed the value of stem cell transplants using a mouse model of Sandhoff disease, a lethal gangliosidosis related to Tay-Sach disease. Joint first authors Jean-Pyo Lee from the Snyder lab and Mylvaganam Jeyakumar of the Platt lab tested the effects of intracranial transplantation of neuronal stem cells into the mice, which lack the enzyme β-hexosaminidase, which helps break down sphingolipids. The mice suffer from a buildup of lysosomal glycosphingolipids, which leads to loss of motor function and early death. After stem cell transplantation, the animals experienced a dramatic improvement in survival, a delayed onset of motor symptoms, and better general health. The researchers showed that they could find electrically active neurons derived from the transplanted cells in the mouse brains. But that was not what saved the mice, since the small number of neurons they found were not enough to account for the dramatic improvements.
Instead, the investigators found the stem cells secreted enough hexosaminidase to decrease toxic levels of gangliosides in the brain. The cells also dampened damaging inflammation, cutting down microglial activation and inflammatory macrophage infiltration, both hallmarks of Sandhoff disease. The mice were not completely cured, though their decline was greatly delayed. This suggests a critical threshold of cells are required that may disappear with time, necessitating multiple transplants.
Because the stem cells clearly helped the neurons, the investigators asked if additional treatments might help the stem cells. To decrease gangliosides even further, they tried a multimodal treatment comprising stem cells and an inhibitor of glycosphingolipid biosynthesis that has proven effective in mouse models of lysosomal storage disease. The two treatments synergistically improved survival, with some mice showing a doubling of lifespan compared to untreated controls, along with delayed onset and improved motor function. The results were repeated when human cells were implanted, either neuronal stem cells from fetal brain or embryonic stem cells differentiated in culture. The cells persisted in mice for 5-6 months without requiring immunosuppression, and without the appearance of tumors.
Their results echo another recent study from the Snyder lab and Richard Sidman, Harvard Medical School, Boston, Massachusetts (see ARF related news story), where transplanted stem cells prevented neurodegeneration by supporting normal gene expression in neurons in the nervous mouse. Of the current study, the authors write, “Given the complexities of CNS development, preserving established circuitry is as important as, and probably safer and more tractable than, attempting to reconstruct new connections.” That means starting treatment early, so that the stem cells can support circuits, rather than be challenged to rebuild them.
SOS: Save Our Stem Cells
Endogenous stem cells also play a support role, providing a source of ready responders to help the brain during aging, or after injury from without or within. In adulthood, hippocampal neural progenitors are born in the dentate gyrus, from where they can migrate and help maintain brain function. The other two papers give a new look at the lives and times of adult neural progenitors, and how we might care for them.
The first, from Rosanne Thomas, Gregory Hotsenpiller, and Daniel Peterson at the Chicago Medical School of the Rosalind Franklin University of Medicine and Science in North Chicago, Illinois, shows that a single episode of acute stress in rats reduces hippocampal neurogenesis by affecting the survival of newly born progenitor cells. The stress, which came when one hapless rat was bullied and beaten up by two others, models acute relational stress in humans. By a careful study of cells at all stages of post-stress neurogenesis, the investigators found that the stress did not affect progenitor proliferation or immediate survival of new cells after 2 days, but instead caused a loss of new cells over the next week. This delayed effect suggests that stress may indirectly harm the environmental stem cell niche in the hippocampus, rather than the stem cells themselves, the authors propose. The surviving cells differentiated normally, but the result was fewer new neurons in the stressed animals.
The study, reported in the March 14 issue of the Journal of Neuroscience, was aimed at elucidating the possible contributions of stress to depression, a disease where reduced neurogenesis may play a role. However, environmental stress, particularly repeated episodes, may play a role in many diseases, including AD, where chronic stress is a risk factor for developing disease.
Could stress also impede neurogenesis in humans? Because it is impossible to look at neurogenesis with the kinds of methods used in animals, Scott Small and colleagues at Columbia University in New York, along with Fred Gage and colleagues at the Salk Institute, La Jolla, California, have developed an MRI correlate of neurogenesis in the dentate gyrus and used it to look at the effects of exercise in a group of volunteers. Their report appears in this week’s PNAS online.
The investigators showed the relationship between blood volume and neurogenesis in mice. They showed that increased cerebral blood volume in the dentate gyrus closely parallels exercised-induced neurogenesis as measured by postmortem measurements of labeled cells in brain. The correlation occurs because neurogenesis is linked to angiogenesis in the region.
They then used a similar MRI technology to look at cerebral blood volume in the hippocampus of humans before and after a 3-month aerobic training regimen. The volunteers showed increased blood volume selectively in the dentate gyrus. The increased blood volume was not an acute response to one training session, but instead correlated measures of increased cardiopulmonary fitness. It also tracked with better cognitive function after the training period. While the results do not prove increased neurogenesis, which the authors point out is impossible to confirm, the restriction of the effect to the dentate gyrus, and the similarities to the effects in mice, support that idea. “These findings show that dentate gyrus cerebral blood volume provides an imaging correlate of exercise-induced neurogenesis, and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging,” the authors write. “The imaging tools presented here are uniquely suited to investigate potential pharmacological modulators of neurogenesis, testing their role in treating depression and in ameliorating the cognitive decline that occurs in all of us as we age,” they conclude.—Pat McCaffrey
References
News Citations
Further Reading
Primary Papers
- Lee JP, Jeyakumar M, Gonzalez R, Takahashi H, Lee PJ, Baek RC, Clark D, Rose H, Fu G, Clarke J, McKercher S, Meerloo J, Muller FJ, Park KI, Butters TD, Dwek RA, Schwartz P, Tong G, Wenger D, Lipton SA, Seyfried TN, Platt FM, Snyder EY. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med. 2007 Mar 11; PubMed.
- Thomas RM, Hotsenpiller G, Peterson DA. Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J Neurosci. 2007 Mar 14;27(11):2734-43. PubMed.
- Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5638-43. PubMed.
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Baylor College of Medicine
The new study by Thomas et al. provides surprising data that even acute bouts of psychosocial stress can have dramatic, long-lasting effects on hippocampal neurogenesis. Using a social dominance paradigm in which young adult male intruders are briefly placed into an older resident colony, they show that a single 20-minute stressor can significantly lower the survival of newborn neurons in the hippocampus. Given this (at least to me) unexpected outcome, the study raises a number of follow-up questions that will be of interest to the Alzheimer community. Perhaps most obvious among them is, what effect does such acute stress, with its resultant decline in hippocampal neurogenesis, have on cognitive behavior? Given the complex nature of the stress response in rodents, it may be hard to relate any changes in behavior directly to a decrease in survival of newborn neurons, but it would nonetheless be an important question to pursue.
What impact acute stress (or hippocampal neurogenesis, for that matter) has on AD is a bit of a stretch from the data at hand. However, if the high rate of cell death among newborn hippocampal progenitor cells (roughly 80 percent die within 4 weeks of mitosis) reflects a population of cells that are teetering on the brink between life and death, and this study shows that acute stress can push them over the edge in even greater numbers than normal, perhaps cells struggling to stay alive in the face of high levels of Aβ might also succumb in greater-than-normal numbers following episodes of acute stress (arguments with caregivers, agitation following a change in routine, etc.). Admittedly, this is an enormous extrapolation from their results, but one that would be interesting to test in mouse models of the disease.
In reading the results, I wonder if the Thomas study might have revealed an even greater impact of stress on neurogenesis than the authors state. Specifically, they find 60 percent more CldU-labeled newborn cells in the hippocampi of stressed animals than in non-stressed controls. The difference in means is just short of statistical significance (p = 0.068), but this experiment used only four animals in each condition. Would they have also observed a significant difference in proliferation as well as survival had they counted more animals? Further, Thomas et al. show that an increased percentage of the newborn cells in stressed rats express a marker of immature neurons (DCX) shortly after cell division (41.9 percent vs. 26.3 percent). Could this suggest that recent stress increases the production of new neurons, but that these cells later die in greater numbers, ultimately resulting in a normal number of surviving mature neurons after the two effects cancel each other out?
Finally, because I have been stumped by this in my own work, I wonder whether the effect of stress on hippocampal neurogenesis is influenced by gender. The paradigm they have used, a form of resident-intruder aggression testing, is most often used with male animals. Females are more accepting of outsiders, and might not reach the same stress levels as males under the same conditions. But if corticosterone were directly administered at the same doses to male and female rats, would they show the same decrement in neurogenesis? And how does neurogenesis in each gender respond to chronic stress? Thomas et al. have shown an almost frightening consequence of a single acute stressor—I hate to think how many new neurons I have lost sweating over deadlines even in my brief academic career.
Life Technologies Corporation
This study by Lee et al. is an extension of several previous studies showing that enzymatic replacement, even at relatively low levels, can provide significant benefit to animals. The effects are quantifiable by biochemical, anatomical, and functional endpoints, though no full or lasting cure has been demonstrated.
In this study the authors make several important points. They suggest that mouse neuronal stem cells (NSCs) may be a useful model of human NSCs, something others in the field have argued may not be true. They also suggest a synergy between therapies and indicate that enzymatic replacement is more important and leads to reduced inflammation and prolonged survival of endogenous neurons. The authors do show some neurogenesis but agree that this cannot account for the global changes seen.
While these studies are encouraging, it is clear that much additional work needs to be done. Longer-term studies, absence of tumorigenesis as was shown to occur with embryonic stem cell transplants in other studies, the potential for longer-term rejection, and the effects of any immune suppressives that may be required need to be evaluated.
No doubt the authors have begun such studies and I look forward to future reports.
University of Illinois at Chicago
The carefully designed study by Thomas et al. is aimed at deepening our understanding of the effect of acute stress on hippocampal neurogenesis by investigating its temporal stage, potentially susceptible to alteration by acute psychosocial stress. Thomas and colleagues show that an acute episode of stress induced by a social dominance paradigm diminishes short-term survival of proliferating cells and long-term survival of newly differentiated neurons in the dentate gyrus. The mechanism underlying acute stress-induced alterations in progenitor cell survival in the hippocampus is largely unknown. In this study, an increase in levels of corticosterone was observed in the serum of animals
exposed to psychosocial stress, but these levels did not correlate with BrdU cell number and measures of aggression (number of bites).
The differential effect of acute stress on proliferation and survival of progenitor cells raises the important question of whether these processes are innate properties of the progenitors, or processes regulated by the neurogenic microenvironment.
In addition, it would be interesting to examine alterations in other measures of hippocampal plasticity following stress. Examination of the effect of acute stress on neurogenesis in the subventricular zone may help us identify whether stress exerts a general effect on neurogenic processes or if these effects are hippocampus-specific. During the last decade, an increasing number of studies demonstrate that stress induces alterations in expression of several neurotrophic factors, such as BDNF, VEGF and FGF-2, in limbic brain regions that play a role in the regulation of cognition. Stress can further lead to depressed synaptic physiology, neuronal atrophy and cell loss in specific brain areas such as the hippocampus and amygdala. Although the physiological response to stress is not fully understood, it becomes increasingly clear that the effects of environmental factors on homeostasis, metabolic pathways, and cellular processes are far reaching. Whether impaired neurogenesis leads to compromised cognitive function in AD and whether a cross-talk exists between Alzheimer pathology and hippocampal neurogenesis are highly relevant questions that have yet to be explored.
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