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Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4
Open accessAbstract
Postnatal/adult neural stem cells (NSCs) within the rodent subventricular zone (SVZ; also called subependymal zone) generate doublecortin (Dcx)(+) neuroblasts that migrate and integrate into olfactory bulb circuitry. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche. It is generally thought that enhancing the neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear whether there are conditions that favour astrogenesis over neurogenesis in the SVZ niche, and whether astrocytes produced there have different properties compared with astrocytes produced elsewhere in the brain. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4), a secreted homopentameric glycoprotein, in contrast to cortical astrocytes, which express low levels of Thbs4. We found that localized photothrombotic/ischaemic cortical injury initiates a marked increase in Thbs4(hi) astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creER(tm)4 lineage tracing demonstrated that it is these SVZ-generated Thbs4(hi) astrocytes, and not Dcx(+) neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production. Consequently, Thbs4 homozygous knockout mice (Thbs4(KO/KO)) showed severe defects in cortical-injury-induced SVZ astrogenesis, instead producing cells expressing Dcx migrating from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular haemorrhage into the brain parenchyma of Thbs4(KO/KO) mice. Taken together, these findings have important implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members have important roles.
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“Top markers that correlated with both NPCs and OPCs included S100a6, Notum, Dbi, and Sfrp1, as well as known V-SVZ qNSC activation and injury-response markers, such as Ascl1, Vim, Thbs4, and Rpl32 (Benner et al., 2013; Dulken et al., 2017; Llorens-Bobadilla et al., 2015; Figure 5B).”
From Single-Cell Analysis of Regional Differences in Adult V-SVZ Neural Stem Cell Lineages (2019) · cites this paper as Benner et al., 2013
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Metadata
- Authors
- Benner, E. J., Luciano, D., Jo, R., Abdi, K., Paez-Gonzalez, P., Sheng, H., Warner, D. S., Liu, C., Eroglu, C., & Kuo, C. T.
- Affiliations
- Duke University (US)
- Corresponding author
- Kuo, Chay T.
- Venue
- Nature
- Published
- 2013-04-24
- Volume
- 497
- Issue
- 7449
- Pages
- 369-373
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3667629
- OpenAlex
- W1988896202
- Cited by
- 282
- References
- 42
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 19 · 2023: 22 · 2022: 14 · 2021: 23 · 2020: 25 · 2019: 25 · 2018: 21 · 2017: 29 · 2016: 25 · 2015: 27 · 2014: 29 · 2013: 6
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (1dp2od004453-01)
- National Institute of Mental Health (R01MH096979)
- National Institute on Drug Abuse (R01DA031833)
- National Institute of General Medical Sciences (T32GM008441)
- National Institute of Neurological Disorders and Stroke (R01NS078192)
- National Institute of Biomedical Imaging and Bioengineering (P41EB015897)
- National Center for Research Resources (P41RR005959)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043494)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- thrombospondin-4, subventricular zone, astrogenesis, Notch signaling, Notch1, cortical injury, astrocyte migration, neurogenesis, neural stem cells, NFIA, glial scar, tissue repair, ischemic injury, lineage tracing, glial scar formation, neuroinflammation, astrocyte heterogeneity, neuroprotection, astrocyte differentiation
- MeSH terms
- Doublecortin Protein, Animals, Astrocytes, Brain Injuries, Cell Movement, Cerebral Cortex, Cerebral Ventricles, Cicatrix, Endocytosis, Neuroglia, Signal Transduction, Mice, Knockout, Cell Lineage, Thrombospondins, Mice, NFI Transcription Factors, Receptor, Notch1, Neural Stem Cells
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