4D imaging analysis of the aging mouse neural stem cell niche reveals a dramatic loss of progenitor cell dynamism regulated by the RHO-ROCK pathway

• Published in: Stem cell reports Vol. 17; no. 2; pp. 245 - 258
• Main Authors: Zhao, Xiuli, Fisher, Elizabeth S., Wang, Yue, Zuloaga, Kristen, Manley, Luke, Temple, Sally
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.02.2022; Elsevier
• Subjects: Aging; Amides - pharmacology; Animals; Cell Movement - drug effects; dynamic progenitor cells; Lateral Ventricles - cytology; Lateral Ventricles - metabolism; Mice; Mice, Transgenic; migration; motility; neural stem cell; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Pyridines - pharmacology; rho GTP-Binding Proteins - metabolism; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; RHO-ROCK pathway; Signal Transduction; stem cell niche; Stem Cell Niche - physiology; subventricular zone; Time-Lapse Imaging; transit amplifying progenitor cell; subventricular zone; neural stem cell; stem cell niche; RHO-ROCK pathway; dynamic progenitor cells; migration; motility; aging; transit amplifying progenitor cell
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2021.12.007

In the adult ventricular-subventricular zone (V-SVZ), neural stem cells (NSCs) give rise to transit-amplifying progenitor (TAP) cells. These progenitors reside in different subniche locations, implying that cell movement must accompany lineage progression, but the dynamic behaviors of adult NSCs and TAPs remain largely unexplored. Here, we performed live time-lapse imaging with computer-based image analysis of young and aged 3D V-SVZ wholemounts from transgenic mice with fluorescently distinguished NSCs and TAP cells. Young V-SVZ progenitors are highly dynamic, with regular process outgrowth and retraction and cell migration. However, these activities dramatically declined with age. An examination of single-cell RNA sequencing (RNA-seq) data revealed age-associated changes in the Rho-Rock pathway that are important for cell motility. Applying a small molecule to inhibit ROCK transformed young into old V-SVZ progenitor cell dynamic behaviors. Hence RHO-ROCK signaling is critical for normal adult NSC and TAP movement and interactions, which are compromised with age, concomitant with the loss of regenerative ability. [Display omitted] •Dynamic behaviors of adult V-SVZ neural progenitor cells captured by 4D analysis•Dramatic loss of process motility, migration, and interactions in the niche with age•Aging changes the RHO-ROCK pathway that regulates motility in the NSC lineage•ROCK inhibition in the young V-SVZ mimics aged progenitor motility How do progenitor cells move in the adult NSC niche? Temple et al. addressed this with live confocal time-lapse imaging. Young NSCs are highly dynamic and motile, but their motility dramatically declines with age. Single-cell RNA-seq and ROCK inhibition reveal that the RHO-ROCK pathway regulates motility changes in the aging niche.