FightAging!
3-10-19

https://www.fightaging.org/archives/...-in-the-brain/

Every month sees the passage of a great many papers describing the computational modeling of cells, protein biochemistry, tissue function, and so forth. All too few of those efforts go any further, moving into real cells and tissues in order to test predictions. Here, it is pleasant to see a group of researchers doing just that and obtaining promising results that add to the growing body of work regarding loss of stem cell activity with age, and means to at least partially reverse that loss. We all have the intuition that, yes of course greatly improved computational capacity has to be helping scientific initiatives move towards rejuvenation in some way, but good demonstrations of real progress remain all too thin on the ground. We are afloat in computational capacity in this modern, connected age, but effective use of those countless processing cycles is quite the different topic.

Researchers have been able to rejuvenate stem cells in the brain of aging mice. The revitalised stem cells improve the regeneration of injured or diseased areas in the brain of old mice. The researchers expect that their approach will provide fresh impetus in regenerative medicine and facilitate the development of stem cell therapies. In order to create as accurate as possible computational models of stem cell behaviour, researchers applied a novel approach. "Stem cells live in a niche where they constantly interact with other cells and extra-cellular components. It is extremely difficult to model such a plethora of complex molecular interactions on the computer. So we shifted perspective. We stopped thinking about what external factors were affecting the stem cells, and started thinking about what the internal state of a stem cell would be like in its precisely defined niche."

The novel approach led to in a new computational model. "Our model can determine which proteins are responsible for the functional state of a given stem cell in its niche - meaning whether it will divide or remain in a state of quiescence. Our model relies on the information about which genes are being transcribed. Modern cell biology technologies enable profiling of gene expression at single cell resolution." From their computational model, researchers identified a molecule called sFRP5 that keeps the neuronal stem cells inactive in old mice, and prevents proliferation by blocking the Wnt pathway crucial for cell differentiation.

Studying stem cells first in a dish and then later directly in mice, a collaborating team then experimentally validated the computational prediction. When neutralising the action of sFRP5, quiescent stem cells did indeed start proliferating more actively. Thus, they were available again to be recruited for the regeneration processes in the aging brain. "With the deactivation of sFRP5, the cells undergo a kind of rejuvenation. As a result, the ratio of active to dormant stem cells in the brain of old mice becomes almost as favourable as in young animals."