Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4 (original) (raw)

Nature volume 497, pages 369–373 (2013)Cite this article

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Abstract

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 circuitry1,2. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche3,4. 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 brain5. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4)6,7, 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 Thbs4hi astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creER tm 4 lineage tracing demonstrated that it is these SVZ-generated Thbs4hi 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 production8. 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 roles9,10.

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Figure 1: SVZ generation of Thbs4hi astrocytes.

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Figure 2: Thbs4hi astrocyte production after photothrombotic cortical injury.

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Figure 3: Notch signalling and regulation of injury-induced SVZ astrogenesis.

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Figure 4: SVZ astrogenesis defects in Thbs4 mutant mice after cortical injury.

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Acknowledgements

We thank D. Melton (Harvard) for R26R-NICD mice; T. Honjo (Kyoto) for RBPjk-flox mice; F. Wang for R26R-tdTomato mice; E. Rawlins (Cambridge) for Foxj1-creER t2 mice; B. Deneen (B.C.M.) and S. Singh for discussions; G. Lyons, R. Andersen, P. Heine, D. Fromme and S. Collins for project assistance; Duke Flow Cytometry Facility for help with FACS; W. Li and Duke Center for In vivo microscopy/brain imaging for MRI analyses; and T. Lechler, A. West and B. Hogan for comments on manuscript. This work was supported by National Biomedical Technology Resource Center Grant P41 RR005959 (C.L.) of P41 EB015897 to Duke Center for In Vivo Microscopy; George and Jean Brumley Endowment, Sontag Foundation, David and Lucile Packard Foundation, March of Dimes, and NIH Director’s New Innovator Award 1 DP2 OD004453-01 (C.T.K.).

Author information

Authors and Affiliations

  1. Department of Pediatrics, George and Jean Brumley Neonatal-Perinatal Research Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Eric J. Benner, Rebecca Jo & Chay T. Kuo
  2. Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Dominic Luciano, Rebecca Jo, Khadar Abdi, Patricia Paez-Gonzalez, Cagla Eroglu & Chay T. Kuo
  3. Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Dominic Luciano, Cagla Eroglu & Chay T. Kuo
  4. Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Huaxin Sheng & David S. Warner
  5. Department of Radiology, Brain Imaging and Analysis Center, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Chunlei Liu
  6. Department of Radiology, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Chunlei Liu
  7. Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Cagla Eroglu & Chay T. Kuo
  8. Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Durham, North Carolina 27710, USA,
    Chay T. Kuo

Authors

  1. Eric J. Benner
  2. Dominic Luciano
  3. Rebecca Jo
  4. Khadar Abdi
  5. Patricia Paez-Gonzalez
  6. Huaxin Sheng
  7. David S. Warner
  8. Chunlei Liu
  9. Cagla Eroglu
  10. Chay T. Kuo

Contributions

E.J.B. performed injury and biochemical experiments; D.L. performed gene expression and live-imaging experiments; K.A. performed in vivo immunoprecipitation experiments; P.P.-G. performed SVZ antibody staining and analyses; R.J., H.S. and D.S.W. assisted with injuries and their analyses; C.L. performed MRI scanning and quantitative analyses; C.E. provided reagents and experimental insight; C.T.K. performed transplantations and conceived the project. E.J.B., D.L. and R.J. assembled figures and C.T.K. wrote the paper. All authors discussed results and commented on the manuscript.

Corresponding author

Correspondence toChay T. Kuo.

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The authors declare no competing financial interests.

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Benner, E., Luciano, D., Jo, R. et al. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.Nature 497, 369–373 (2013). https://doi.org/10.1038/nature12069

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Editorial Summary

Stem-cell-mediated recovery from brain injury

The subventricular zone (SVZ) of the rodent brain is known to host precursor cells that can generate neurons or glia, depending on the microenvironment. The question arises, might activating this niche following brain injury play a role in tissue repair? Here, Chay Kuo and colleagues identify a specific population of SVZ-generated astrocytes in mice that increases in number post-injury. These activated astrocytes migrate to the site of injury, unlike their cortex-generated counterparts. This robust post-injury response requires Notch signalling, and when this population of astrocytes is disrupted tissue recovery is compromised.