Publication Date:
2013-04-26
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667629/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667629/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Benner, Eric J -- Luciano, Dominic -- Jo, Rebecca -- Abdi, Khadar -- Paez-Gonzalez, Patricia -- Sheng, Huaxin -- Warner, David S -- Liu, Chunlei -- Eroglu, Cagla -- Kuo, Chay T -- DP2 OD004453/OD/NIH HHS/ -- DP2 OD004453-01/OD/NIH HHS/ -- K12 HD043494/HD/NICHD NIH HHS/ -- P41 EB015897/EB/NIBIB NIH HHS/ -- P41 RR005959/RR/NCRR NIH HHS/ -- R01 DA031833/DA/NIDA NIH HHS/ -- R01 MH096979/MH/NIMH NIH HHS/ -- R01 NS078192/NS/NINDS NIH HHS/ -- T32 GM008441/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 16;497(7449):369-73. doi: 10.1038/nature12069. Epub 2013 Apr 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉George and Jean Brumley Neonatal-Perinatal Research Institute, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23615612" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Astrocytes/*cytology/*metabolism
;
Brain Injuries/*metabolism/*pathology
;
Cell Lineage
;
Cell Movement
;
Cerebral Cortex/cytology/metabolism/pathology
;
Cerebral Ventricles/*cytology
;
Cicatrix/metabolism/pathology
;
Endocytosis
;
Mice
;
Mice, Knockout
;
NFI Transcription Factors/metabolism
;
Neural Stem Cells/cytology
;
Neuroglia/cytology/metabolism/pathology
;
Receptor, Notch1/*metabolism
;
Signal Transduction
;
Thrombospondins/deficiency/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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