TY - JOUR
T1 - Neurogenic niche microglia undergo positional remodeling and progressive activation contributing to age-associated reductions in neurogenesis
AU - Solano Fonseca, Rene
AU - Mahesula, Swetha
AU - Apple, Deana M.
AU - Raghunathan, Rekha
AU - Dugan, Allison
AU - Cardona, Astrid
AU - O'Connor, Jason
AU - Kokovay, Erzsebet
N1 - Funding Information:
Acknowledgments This work received computational support from Computational System Biology Core, funded by the National Institute on Minority Health and Health Disparities (G12MD 007591) from the National Institutes of Health. Images were generated in the Core Optical Imaging Facility, which is supported by UTHSCSA, NIH-NCI P30 CA54174 (CTRC at UTHSCSA) and NIH-NIA P01AG19316. Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UTHSCSA, NIH-NCI P30 CA 054174-20 (CTRC at UTHSCSA), and UL1 TR001120 (CTSA grant). This work was supported in part by the William and Ella Owens Medical Research Foundation and Nathan Shock Center of Excellence in Basic Biology of Aging to EK and by the National Institutes of Health grant SC1GM095426 to AEC.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Neural stem cells (NSCs) exist throughout life in the ventricular-subventricular zone (V-SVZ) of the mammalian forebrain. During aging NSC function is diminished through an unclear mechanism. In this study, we establish microglia, the immune cells of the brain, as integral niche cells within the V-SVZ that undergo age-associated repositioning in the V-SVZ. Microglia become activated early before NSC deficits during aging resulting in an antineurogenic microenvironment due to increased inflammatory cytokine secretion. These age-associated changes were not observed in non-neurogenic brain regions, suggesting V-SVZ microglia are specialized. Using a sustained inflammatory model in young adult mice, we induced microglia activation and inflammation that was accompanied by reduced NSC proliferation in the V-SVZ. Furthermore, in vitro studies revealed secreted factors from activated microglia reduced proliferation and neuron production compared to secreted factors from resting microglia. Our results suggest that age-associated chronic inflammation contributes to declines in NSC function within the aging neurogenic niche.
AB - Neural stem cells (NSCs) exist throughout life in the ventricular-subventricular zone (V-SVZ) of the mammalian forebrain. During aging NSC function is diminished through an unclear mechanism. In this study, we establish microglia, the immune cells of the brain, as integral niche cells within the V-SVZ that undergo age-associated repositioning in the V-SVZ. Microglia become activated early before NSC deficits during aging resulting in an antineurogenic microenvironment due to increased inflammatory cytokine secretion. These age-associated changes were not observed in non-neurogenic brain regions, suggesting V-SVZ microglia are specialized. Using a sustained inflammatory model in young adult mice, we induced microglia activation and inflammation that was accompanied by reduced NSC proliferation in the V-SVZ. Furthermore, in vitro studies revealed secreted factors from activated microglia reduced proliferation and neuron production compared to secreted factors from resting microglia. Our results suggest that age-associated chronic inflammation contributes to declines in NSC function within the aging neurogenic niche.
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U2 - 10.1089/scd.2015.0319
DO - 10.1089/scd.2015.0319
M3 - Article
C2 - 26857912
AN - SCOPUS:84962339344
VL - 25
SP - 542
EP - 555
JO - Stem Cells and Development
JF - Stem Cells and Development
SN - 1547-3287
IS - 7
ER -