Regenerating Memory With Neural Stem Cells

Summary: Researchers hint that a new technique of grafting neural stem cells into the hippocampus could help restore memory.

Source: Texas A&M.

Researchers look for better ways to reduce memory loss in people with age-related disorders.

Although brains—even adult brains—are far more malleable than we used to think, they are eventually subject to age-related illnesses, like dementia, and loss of cognitive function.

Someday, though, we may actually be able to replace brain cells and restore memory. Recent work 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, and his team at the Texas A&M Health Science Center College of Medicine hints at this possibility with a new technique of preparing donor neural stem cells and grafting them into an aged brain.

Shetty and his team took neural stem cells and implanted them into the hippocampus—which plays an important role in making new memories and connecting them to emotions—of an animal model, essentially enabling them to regenerate tissue. Findings were published in the journal Stem Cells Translational Medicine.

“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.

“We’re very excited to see that the aged hippocampus can accept grafted neural stem cells as superbly as the young hippocampus does and this has implications for treating age-related neurodegenerative disorders,” said Bharathi Hattiangady, assistant professor at the Texas A&M College of Medicine and co-first author of the study. “It’s interesting that even neural stem cell niches can be formed in the aged hippocampus.”

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 great benefit for preventing memory loss in aging, his latest work demonstrates a way to affect the function of the hippocampus more directly.

For this latest research, 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.”

“What was really exciting is that in both old and young brains, a small percentage of the grafted cells retained their ‘stemness’ feature and continuously produced new neurons,” Hattiangady said.

This is called creating a new ‘niche’ of neural stem cells, and these niches seemed to be functioning well. “They are 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. “We have a new technique of preparing the donor neural stem cells,” Shetty said. “That’s why this result has never been seen before.”

The researchers did this work using 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 and continuously produce new neurons that migrate to the olfactory system. These stem cells also respond to injury signals in conditions such as stroke and traumatic brain injury and replace some of the lost cerebral cortical neurons.

For this latest research, 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. NeuroscienceNews.com image is adapted from the Texas A&M press release.

Even a small piece is good enough to expand in culture, so the procedure isn’t terribly invasive, but in the future, a skin cell might suffice, as similar neural stem cells can be obtained in large numbers from skin. It’s been well known in medical science that a number of cells in the body—including those of the skin—can be modified in such a way to create induced pluripotent stem cells. With these cells, scientists can do any number of things, including making neural stem cells that will make both more of themselves and new neurons. “You don’t have to get the cells from the brain, you can just take a skin biopsy and push them into neural stem cells,” Shetty said.

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.”

About this neurology research article

Funding: This study was funded by State of Texas Emerging Technology Fund; , I01 BX002351; R01 NS054780.

Source: Holly Shive – Texas A&M
Image Source: This NeuroscienceNews.com image is adapted from the Texas A&M press release.
Original Research: Full open access research for “Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus” by Ashok K. Shetty and Bharathi Hattiangady in Stem Cells Translational Medicine. Published online May 18 2016 doi:10.5966/sctm.2015-0270

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]Texas A&M. “Regenerating Memory With Neural Stem Cells.” NeuroscienceNews. NeuroscienceNews, 14 June 2016.
<https://neurosciencenews.com/neural-stem-cells-memory-4466/>.[/cbtab][cbtab title=”APA”]Texas A&M. (2016, June 14). Regenerating Memory With Neural Stem Cells. NeuroscienceNew. Retrieved June 14, 2016 from https://neurosciencenews.com/neural-stem-cells-memory-4466/[/cbtab][cbtab title=”Chicago”]Texas A&M. “Regenerating Memory With Neural Stem Cells.” https://neurosciencenews.com/neural-stem-cells-memory-4466/ (accessed June 14, 2016).[/cbtab][/cbtabs]


Abstract

Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus

As clinical application of neural stem cell (NSC) grafting into the brain would also encompass aged people, critical evaluation of engraftment of NSC graft-derived cells in the aged hippocampus has significance. We examined the engraftment and differentiation of alkaline phosphatase-positive NSCs expanded from the postnatal subventricular zone (SVZ), 3 months after grafting into the intact young or aged rat hippocampus. Graft-derived cells engrafted robustly into both young and aged hippocampi. Although most graft-derived cells pervasively migrated into different hippocampal layers, the graft cores endured and contained graft-derived neurons expressing neuron-specific nuclear antigen (NeuN) and γ-amino butyric acid in both groups. A fraction of migrated graft-derived cells in the neurogenic subgranular zone-granule cell layer also expressed NeuN. Neuronal differentiation was, however, occasionally seen amid graft-derived cells that had migrated into non-neurogenic regions, where substantial fractions differentiated into S-100β+ astrocytes, NG2+ oligodendrocyte progenitors, or Olig2+ putative oligodendrocytes. In both age groups, graft cores located in non-neurogenic regions displayed many doublecortin-positive (DCX+) immature neurons at 3 months after grafting. Analyses of cells within graft cores using birth dating and putative NSC markers revealed that DCX+ neurons were newly born neurons derived from engrafted cells and that putative NSCs persisted within the graft cores. Thus, both young and aged hippocampi support robust engraftment and similar differentiation of SVZ-NSC graft-derived cells. Furthermore, some grafted NSCs retain the “stemness” feature and produce new neurons even at 3 months after grafting, implying that grafting of SVZ-NSCs into the young or aged hippocampus leads to establishment of new neurogenic niches in non-neurogenic regions.

Significance
The results demonstrate that advanced age of the host at the time of grafting has no major adverse effects on engraftment, migration, and differentiation of grafted subventricular zone-neural stem cells (SVZ-NSCs) in the intact hippocampus, as both young and aged hippocampi promoted excellent engraftment, migration, and differentiation of SVZ-NSC graft-derived cells in the present study. Furthermore, SVZ-NSC grafts showed ability for establishing neurogenic niches in non-neurogenic regions, generating new neurons for extended periods after grafting. This phenomenon will be beneficial if these niches can continuously generate new neurons and glia in the grafted hippocampus, as newly generated neurons and glia are expected to improve, not only the microenvironment, but also the plasticity and function of the aged hippocampus. Overall, these results have significance because the potential application of NSC grafting for treatment of neurodegenerative disorders at early stages of disease progression and age-related impairments would mostly involve aged persons as recipients.

“Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus” by Ashok K. Shetty and Bharathi Hattiangady in Stem Cells Translational Medicine. Published online May 18 2016 doi:10.5966/sctm.2015-0270

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