Researchers from the University of Luxembourg and the German Cancer Research Center have rejuvenated stem cells in the brains of old mice. The rejuvenated stem cells appear to improve regeneration in areas of damaged or diseased brain tissue.
A new way to model stem cells
A new study that was published in the journal Cell sheds light on why many stem cell populations in aged brains stop dividing and enter a dormant state known as quiescence. Quiescent stem cells have ceased to divide, so they no longer support the tissues of which they are part and play no role in regenerating damaged tissue by supplying fresh cells to replace losses. As we age, an increasing number of stem cells, not just in the brain, enter this quiescent state and impair our ability to heal injury and recover from diseases.
The team used in silico modeling to create a simulation of stem cell behavior that was as close as possible to the real thing. Stem cells occupy a special pocket known as a niche, which protects them while allowing them to interact with the cells of their local tissues along with extracellular components.
Modeling this complex relationship between stem cells, their niches, and the many exterior interactions is highly challenging, so the team chose a different approach. Rather than focusing on how external factors and interactions were affecting the stem cells, they shifted to thinking about the internal states of stem cells, their niches, and the protein interactions taking place there.
This new approach, developed by Dr. Srikanth Ravichandran, gives researchers the opportunity to identify the specific proteins that regulate the function of a given stem cell in its niche. Modern technology allows gene expression profiling to be conducted on single cells, giving a highly detailed picture of what is happening on a cell-by-cell basis. These techniques allow researchers to determine if a stem cell will continue to divide or if it will fall into a dormant, quiescent state.
It has been somewhat of a mystery why many stem cells in aged brains enter and remain in this quiescent state, but this new computational model has helped to explain why. With it, researchers have determined that a molecule called sFRP5 is responsible for keeping murine stem cells in a dormant state by inhibiting the Wnt pathway.
The Wnt signaling pathway is an evolutionarily conserved pathway that regulates critical aspects of cell fate determination, cell migration, cell polarity, and stem cell differentiation. In broad terms, the Wnt pathway is a growth and development mechanism that guides our bodies through various life stages and helps to ensure that organs and cells are in the right place.
Rejuvenating aged brains
The next step was for the researchers to take this information and put it to the test, first using cells in a petri dish and then moving to aged mice. When they blocked the activity of the sFRP5 molecule, they observed that stem cells that were previously in a quiescent state became active and resumed proliferation. This showed that the stem cells were once again actively contributing to the regeneration process in the brains of old mice and thereby helping to improve tissue function.
The researchers also observed that the ratio of quiescent to active stem cells in the brains of these aged mice was similar to that of younger animals, so this suggests that they were at least partially rejuvenated.
These results pave the way for stem cell therapies that may help to repair brain damage from strokes or neurodegenerative diseases such as Alzheimer’s. The new computational model should also be useful for modeling the stem cells in other tissues and organs and help us to better understand how we can control quiescence and encourage regeneration. This opens the door for regenerative medicine and the in situ repair of damaged organs, which has big implications for aging research.
In silico modeling and, in general, the advances being made in deep learning are helping to accelerate our understanding of biology and will likely continue to shape the future of aging research.
 Georgios Kalamakis, Daniel Brüne, Srikanth Ravichandran, Jan Bolz, Wenqiang Fan, Frederik Ziebell, Thomas Stiehl, Francisco Catalá-Martinez, Janina Kupke, Sheng Zhao, Enric Llorens-Bobadilla, Katharina Bauer, Stefanie Limpert, Birgit Berger, Urs Christen, Peter Schmezer, Jan Philipp Mallm, Benedikt Berninger, Simon Anders, Antonio del Sol, Anna Marciniak-Czochra, Ana Martin-Villalba. Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain. Cell, 2019; DOI: 10.1016/j.cell.2019.01.040