17 March 2007. 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.
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; [Epub ahead of print] Abstract
Thomas RM, Hotsenpiller G, Peterson DA. Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J. Neurosci. 2007 March 14; 27(11):2734-2743. Abstract
Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. PNAS Early Edition, pending. Abstract