Replacing Neural Stem Cells in the Aging Hippocampus

Today I'll point out progress towards an as yet unrealized category of stem cell treatments involving the wholesale replacement of entire stem cell populations and their niches, to remove age-related damage and sustain tissue maintenance for the long term. This will become an essential component for any future rejuvenation toolkit. From a stem cell perspective, rejuvenation has two components: firstly revert the root causes of signaling changes in blood and tissues that result in stem cell populations becoming less active; secondly, replace the stem cells themselves, scores of different types in different locations, to clear out damaged cells. The root cause of signaling changes in old individuals is, collectively, all of the forms of damage listed in the SENS proposals for rejuvenation treatments - a lot of work is yet to be accomplished there to reach even the initial goals of prototype treatments across the board. Nonetheless, it is still the case that replacement of aged stem cell populations with undamaged, pristine stem cells created from the patient's own cells is an important target for future development in the stem cell field.

Most stem cell therapies in use today are actually far removed from this goal: the transplanted cells do not live long, and do not integrate with recipient tissues. They achieve beneficial effects through a temporary alteration of the signaling environment that spurs regeneration and reduces inflammation. In effect the transplant temporarily overrules the evolved reaction to being aged and damaged and puts sleeping cells back to work - but without fixing that low level damage. So there can be some degree of rebuilding of worn tissues and organs, but the causes of aging are still present and continue to cause harm: cross-links, mitochondrial mutations, and so forth.

There are exceptions to the outcome of benefits through signaling mechanisms, however, and these exceptions include types of therapy in which cells are transplanted into the brain. Some of the earliest stem cell transplants trialed in humans aimed to treat Parkinson's disease, for example, and at least some of the transplanted cells survived and integrated into the brains of patients for the long term. This is still a considerable distance removed from a controlled repopulation of stem cell niches in all of the right places and with cells that will pick up tissue maintenance activities in exactly the right ways, but it is a step in the right direction. In the research materials linked below, scientists report on further progress along these lines, and that they were able to create new stem cell niches in brain tissue seems like an important advance:

Regenerating Memory with Neural Stem Cells

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 hints at this possibility with a new technique of preparing donor neural stem cells and grafting them into an aged brain. The team took neural stem cells and implanted them into the hippocampus - which plays an important role in making new memories and connecting them to emotion - of an animal model, essentially enabling them to regenerate tissue.

"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. It's interesting that even neural stem cell niches can be formed in the aged hippocampus." 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. 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."

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. 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. That's an area that we'd like to study in the future."

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.

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.


"Grafts showed ability for establishing neurogenic niches in non-neurogenic regions, generating new neurons for extended periods after grafting". That's particularly heartening, as is the age of the animals used. I've always worried that stem cell treatments might not work in aged tissues. It seems that at least sometimes they do.

Posted by: KC at June 17th, 2016 5:03 PM

Yeah they do. Here is some Alzheimers work our researcher Dr Stolzing was involved in. Shrinking of plauques and engraftment are seen.Alexandra believes there are additional improvements that can be made to this to boost its benefits further.

Posted by: Steve Hill at June 18th, 2016 5:15 AM

@Steve @KC: well, it depends on which "stem cells" and what you mean by "work." As you (Steve) know, the aged niche often doesn't support resident tissue stem cell activity well, initially largely due to reversible factors in the systemic environment and later progressively more so due to structural damage to the niche (alongside progressively more irreversible damage to the resident tissue stem cells themselves). Over and beyond that, the aged tissue itself often doesn't "take" replacement stem cells for a variety of reasons, some of which relate to aging and some of which are intrinsic to the tissue itself even when young. In the case of the brain, non-neurogenic areas of the brain don't take true replacement stem cells because they were never actually evolved to have such cells available. The hippocampus, happily, is a neurogenic area and so ought to be one of the easier areas to maintain and replenish; the adult neocortex is not, and thus will require sophisticated engineering to get stem, progenitor, and/or pluripotent stem-cell-derived neurons to engraft and incorporate into existing circuitry to maintain and restore brain structure.

The example you (Steve) gave is a different matter: these are MSCs, not new neurons to replace old ones, and presumably work by delivering trophic support and other paracrine factors, and perhaps by helping the local microvasculature. (You say that the cells here engrafted: that's not in the abstract - is it in the full text)? Obviously, however, reducing the size of pyroglutamate-modified Abeta plaque is a promising result, and it'll be important to get a handle on the mechanism and explore the approach further.

Posted by: Michael at June 19th, 2016 11:20 AM

"In the case of the brain, non-neurogenic areas of the brain don't take true replacement stem cells because they were never actually evolved to have such cells available."

Of all the terrifying and profound things you've informed us of, this is one of the most terrible. How much effect has this little factoid had on our politics, our culture, our ability to reason and cope with changing environments? How much does it do to our society when people's dwindling supplies of neurons can't rearrange themselves enough? What does it do to you, me, and everyone else reading this?

I'd offer the first person to alter this situation some kind of prize, but anyone who can put functioning neocortical cells in his own head doesn't need one.

Posted by: Slicer at June 20th, 2016 11:11 AM

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