A Dip in the Neural Stem Cell Pool(s)

 

Back in my undergrad days, I worked as a student researcher at the Broad CIRM Center for Stem Cell and Regenerative Medicine at USC, and in June of this year one of the projects I assisted with was published in Cell Stem Cell. So I wanted to make a blog post about this because 1) neural stem cells are really cool and 2) this paper is so niche that, unless I blog about it, there is a very good chance that nobody will ever read it.

So, what exactly was this project? We were looking at the effects of normal aging on adult neurogenesis. As some of you in the MSBS program may recall from TBL 1, there are 2 regions where neurogenesis is thought to occur: the subventricular zone and the subgranular zone of the hippocampus (we were interested in the latter). At a population level, we know that the neural stem cell (NSC) pool decreases with age, but little is known about the changes that are occurring at a cellular level. So the goal was to answer two main questions: What is happening to individual NSCs over time? And what is driving this change?

Using transgenic mice, we performed in-vivo clonal analysis (which is a nice way of saying that we harvested their brains and fluorescently stained them) and identified two discrete populations of neural stem cells: short-term NSCs and long-term NSCs. Short-term NSCs are abundant in the young brain because they divide rapidly, but they also deplete quickly. On the other hand, Long-term NSCs are maintained for longer, but they experience increased quiescence with each subsequent division. Basically, it takes longer and longer for them to divide, and this eventually drives the NSC pool out of homeostasis.

So what exactly is driving this increased quiescence? After I graduated, the lab performed single-cell RNA sequencing to figure out what transcriptomic changes were occurring, and they found that one gene, Abl1, a tyrosine-protein kinase, is upregulated in aging (there were others, but they chose to focus on this one). Using imatinib, a common cancer drug, they inhibited Abl1 activity and found that it increased NSC activation in middle-aged brains, suggesting that it may play a role in the NSC quiescence.

Obviously, there are limitations to this study. For one, imatinib could be working on any number of targets, so it doesn’t necessarily prove that Abl1 is the root of all evil. Also, this study was performed in mice, which are a little different than humans. Nevertheless, I think this research shows just how dynamic our brains are and I hope it inspires some new directions in regenerative medicine.  

 

References:

Ibrayeva, A., Bay, M., Pu, E., Jörg, D. J., Peng, L., Jun, H., Zhang, N., Aaron, D., Lin, C., Resler, G., Hidalgo, A., Jang, M.-H., Simons, B. D., & Bonaguidi, M. A. (2021). Early stem cell aging in the mature brain. Cell Stem Cell, 28(5), 955–966. https://doi-org.dml.regis.edu/10.1016/j.stem.2021.03.018