Department of Genetics, Stanford University, Stanford, CA, USA.
Stanford Biophysics Program, Stanford University, Stanford, CA, USA.
Nat Aging. 2023 Jul;3(7):866-893. doi: 10.1038/s43587-023-00449-3. Epub 2023 Jul 13.
The regenerative potential of brain stem cell niches deteriorates during aging. Yet the mechanisms underlying this decline are largely unknown. Here we characterize genome-wide chromatin accessibility of neurogenic niche cells in vivo during aging. Interestingly, chromatin accessibility at adhesion and migration genes decreases with age in quiescent neural stem cells (NSCs) but increases with age in activated (proliferative) NSCs. Quiescent and activated NSCs exhibit opposing adhesion behaviors during aging: quiescent NSCs become less adhesive, whereas activated NSCs become more adhesive. Old activated NSCs also show decreased migration in vitro and diminished mobilization out of the niche for neurogenesis in vivo. Using tension sensors, we find that aging increases force-producing adhesions in activated NSCs. Inhibiting the cytoskeletal-regulating kinase ROCK reduces these adhesions, restores migration in old activated NSCs in vitro, and boosts neurogenesis in vivo. These results have implications for restoring the migratory potential of NSCs and for improving neurogenesis in the aged brain.
脑干细胞龛的再生潜力在衰老过程中会下降。然而，这种衰退的机制在很大程度上尚不清楚。在这里，我们在体内衰老过程中对神经发生龛细胞的全基因组染色质可及性进行了表征。有趣的是，在静止的神经干细胞（NSC）中，与黏附和迁移基因相关的染色质可及性随年龄增长而降低，但在激活（增殖）的 NSCs 中随年龄增长而增加。在衰老过程中，静止和激活的 NSCs 表现出相反的黏附行为：静止的 NSCs 变得不那么黏附，而激活的 NSCs 变得更黏附。年老的激活 NSCs 在体外的迁移能力也下降，体内神经发生龛外的动员能力也减弱。使用张力传感器，我们发现衰老会增加激活的 NSCs 产生力的黏附。抑制细胞骨架调节激酶 ROCK 可减少这些黏附，恢复体外老年激活 NSCs 的迁移能力，并促进体内神经发生。这些结果对恢复 NSCs 的迁移潜力和改善老年大脑中的神经发生具有重要意义。
