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Scientists Rejuvenate Stem Cells in Aging Mice Brains

LUXEMBOURG, March 2019— Scientists from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg and from the German Cancer Research Center (DKFZ) have been able to rejuvenate stem cells in the brains of aging mice.

The revitalized stem cells improve the regeneration of injured or diseased areas in the brains of old mice. The researchers expect that their approach will provide fresh impetus in regenerative medicine and facilitate the development of stem cell therapies. Their results were published in Cell.

All cells making up our organs originate from stem cells. With age, however, the stem cells of living organisms lose their ability to proliferate. Many of them lapse into a permanent state of quiescence.

In order to create computational models of stem cell behavior that are as accurate as possible, the LCSB’s Computational Biology Group led by Antonio del Sol, Ph.D., applied a novel approach. “Stem cells live in a niche where they constantly interact with other cells and extracellular components. It is extremely difficult to model such a plethora of complex molecular interactions on the computer. So we shifted perspective,” he explained. “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 developed by Srikanth Ravichandran, Ph.D., also of the Computational Biology Group. “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,” he said. “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.”

It was previously unknown why most of the stem cells in the brains of old mice remain in a state of quiescence. From their computational model, the researchers at the LCSB 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.

A rejuvenation for stem cells

Then the long-standing expertise in neural stem cells of the collaborators at the German Cancer Research Center (DKFZ) came in: Studying stem cells first in a dish and then later directly in mice, they could experimentally validate the computational prediction. When neutralizing the action of sFRP5, the 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,” Dr. del Sol said. “As a result, the ratio of active to dormant stem cells in the brain of old mice becomes almost as favorable as in young animals.

“Our results constitute an important step toward the implementation of stem cell-based therapies, for instance for neurodegenerative diseases,” he added. “We were able to show that, with computational models, it is possible to identify the essential features that are characteristic of a specific state of stem cells.”

This approach is not limited to studying the brain. It can also be used to model stem cells of other organs in the body. “The hope is that this will open avenues for regenerative medicine,” Dr. del Sol concluded.


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DOI: 10.1016/j.cell.2019.01.040