The human brain, as it turns out, is far more malleable than we once thought. Even adult brains. But they are subject to age-related diseases and disorders, such as dementia and diminished cognitive function.
There is hope that medical science may be able to replace brain cells and restore memory in aging patients thanks to new discoveries in neural stem cell techniques. Researchers at the Texas A&M Health Science Center College of Medicine recently published new findings in the journal Stem Cells Translational Medicine that suggests a new technique for preparing donor neural stem cells and grafting them into an aged brain can regenerate tissue that has succumbed to structural, chemical, and functional changes, as well as a host of neurocognitive changes that can be attributed to aging.
The study, titled “Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus,” was led by Ashok K. Shetty, Ph.D., a professor in the Department of Molecular and Cellular Medicine. associate director of the Institute for Regenerative Medicine, and research career scientist at the Central Texas Veterans Health Care System.
Shetty and his team at Texas A&M focus on the aged hippocampus, which plays an important role in making new memories and connecting them to emotions. They took healthy donor neural stem cells and implanted them into the hippocampus of an animal model, essentially enabling them to regenerate tissue.
The hippocampus in the aging brain
"We chose the hippocampus because it's so important in learning, memory and mood function," Shetty said. "We're interested in understanding aging in the brain, especially in the hippocampus, which seems particularly vulnerable to age-related changes."
The volume of this part of the brain seems to decrease during the aging process, and this decrease may be related to age-related decline in neurogenesis (production of new neurons) and the memory deficits some people experience as they grow older.
The aged hippocampus also exhibits signs of age-related degenerative changes in the brain, such chronic low-grade inflammation and increased reactive oxygen species.
Bharathi Hattiangady, assistant professor at the Texas A&M College of Medicine and co-first author of the study said his team was excited to discover that the aged hippocampus can accept grafted neural stem cells as well as the young hippocampus does, a discovery that has significant implications for treating age-related neurodegenerative disorders.
"It's interesting that even neural stem cell niches can be formed in the aged hippocampus," Hattiangady says.
Shetty's previous research focused on the benefits of resveratrol (an antioxidant that is famously found in red wine and the skin of red grapes, as well as in peanuts and some berries) to the hippocampus. Although the results indicated important benefits for preventing memory loss in aging brains, his newest work demonstrates a way to affect the function of the hippocampus more directly.
Neural stem cell grafting
In this new study, the team found that the neural stem cells engrafted well onto the hippocampus in the young animal models (which was expected) as well as the older ones that would be, in human terms, about 70 years old. Not only did these implanted cells survive, they divided several times to make new cells.
"They had at least three divisions after transplantation," Shetty said. "So the total yield of graft-derived neurons and glia (a type of brain cell that supports neurons) were much higher than the number of implanted cells, and we found that in both the young and aged hippocampus, without much difference between the two."
In both old and young brains, a small percentage of the grafted cells retained their stemness feature—an essential characteristic of a stem cell that distinguishes it from ordinary cells—and continuously produced new neurons. This is called creating a new 'niche' of neural stem cells, and these niches seemed to be functioning well. They were still producing new neurons at least three months after implantation, and these neurons are capable of migrating to different parts of the brain.
Past efforts to rejuvenate brains using fetal neurons in this way weren't nearly as successful. Immature cells, such as neural stem cells, seem to do a better job because they can tolerate the hypoxia (lack of oxygen) and trauma of the brain grafting procedure better than post-mitotic or relatively mature neurons. When researchers tried in the past to implant these partially differentiated cells into the aged hippocampus, they didn't do nearly as well. The research team used a new technique of preparing the donor neural stem cells, which Shetty says is why this result has never been seen before.
The researchers used donor cells from the sub-ventricular zone of the brain, an area called the "brain marrow," because it is analogous to bone marrow in that it holds a number of neural stem cells that persist throughout life. These neural stem cells continuously produce new neurons that migrate to the olfactory system. They also respond to injury signals in conditions such as stroke and traumatic brain injury and replace some of the lost cerebral cortical neurons.
Induced pluripotent cells from skin
Even a small stem cell sample is good enough to expand in culture, so the procedure isn't terribly invasive. However, in the future, a single skin cell might suffice, as similar neural stem cells can be obtained in large numbers from skin. In fact, it is well known in medical science that a number of cells in the body—including skin cells—can be modified in such a way to create induced pluripotent stem cells.
With these cells, scientists can do any number of things, such as making neural stem cells that will make both more of themselves, and make new neurons. It’s not necessary to get the cells from the brain, just take a skin biopsy and push them into neural stem cells, according to Shetty.
Although the way the grafted cells thrived is promising, there is still a good deal of work to be done to determine if the extra grey matter actually improves cognition.
"Next, we want to test what impact, if any, the implanted cells have on behavior and determine if implanting neural stem cells can actually reverse age-related learning and memory deficits," Shetty said. "That's an area that we'd like to study in the future.
“I'm always interested in ways to rejuvenate the aged brain to promote successful aging, which we see when elderly persons exhibit normal cognitive function and the ability to make memories."