Newborn Healers—Novel Astrocytes Repair Brain Injury

When leaky blood vessels damage the brain, the organ’s stem cell niche dispatches a specialist crew of astrocytes to stop the bleeding, reports a paper in the April 24 Nature online. These novel glia appear essential for proper recovery. The work supports the emerging idea that glia, like neurons, come in many varieties. “Do not look at all astrocytes as though they are the same population,” said senior study author Chay Kuo of Duke University in Durham, North Carolina. Other researchers wondered what this might have to do with reactive astrocytosis in neurodegenerative diseases such as Alzheimer's.

Kuo and first author Eric Benner, who now heads his own lab at Duke, were not expecting to study astrocytes. They planned to trace newborn neurons from the mouse subventricular zone (SVZ) in response to injury. The researchers presumed stem cells would produce neurons to fill in the damaged area; others have reported neuron efflux from the SVZ following ischemia (Thored et al., 2006). Kuo developed a system to label neural stem cells in the SVZ and their progeny with the red fluorescent protein tdTomato (see ARF related news story on Kuo et al., 2006). Benner created a blood clot in the cortex close to the SVZ and subsequently examined the brains for cells lit up with tdTomato. He and Kuo were surprised when all they saw were astrocytes. These arose a few days after the injury and migrated to the damaged site.

Were these migratory astrocytes typical, or might there be something special about them? Scientists have come to suspect that astrocytes are a diverse group of cells with many subclasses (Hochstim et al., 2008). Duke collaborator Cagla Eroglu suggested looking for different thrombospondin proteins to distinguish the SVZ astrocytes. Eroglu studies thrombospondins, which are extracellular matrix proteins involved in cell-cell interactions. Astrocytes secrete thrombospondins to nudge neurons to form synapses (see ARF related news story on Christopherson et al., 2005; Eroglu et al., 2009; Eroglu, 2009). Some thrombospondins influence wound healing and angiogenesis (Adams and Lawler, 2011). Trying these proteins was a “shot in the dark,” Kuo admitted, but it hit a bullseye. The astrocytes that responded to injury expressed 100-fold more thrombospondin 4 than typical cortical astrocytes. “They are not garden-variety astrocytes,” Kuo said.

Thrombospondin 4 turned out to be more than a convenient marker; it was required for astrocytes to proliferate in response to the blood clot. In thrombospondin 4 knockout mice, the injury continually bled. “We think that these [newborn] astrocytes are there to make the bleeding stop before recovery can begin,” Kuo said. The paper supports previous work indicating that astrocytes protect the brain during trauma and ischemia, noted Michael Sofroniew of the University of California, Los Angeles, in an e-mail to Alzforum (Faulkner et al., 2004).

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Newborn Healers
In control mice (left), thrombospondin 4-positive astrocytes (red) from the SVZ migrate to injury sites, sealing off blood vessels (green). In mice lacking thrombospondin 4, astrocytes are few and disorganized, and blood leaks into the brain tissue. Image courtesy of Nature

What are the implications for human injury and disease? The first task, Kuo noted, will be to determine whether people have a similar population of thrombospondin 4-expressing astrocytes. If so, therapeutics to activate them following a brain injury might be beneficial.

Might these cells protect against neurodegeneration? “To date, most of the work on astrocytes in the field of neurodegenerative diseases such as Alzheimer’s has focused on ways astrocytes contribute to degeneration,” Sofroniew noted. “Instead, if the authors are correct, then these newly generated astrocytes … would seem most likely to be neuroprotective.”

Kuo speculated that SVZ-derived astrocytes might fight neuroinflammation by extinguishing small bleeds associated with aging. Perhaps, he suggested, failure of this repair mechanism could contribute to neurological disease. The diversity of astrocytes implies that treatments might have to be targeted to specific subclasses, he said.

“I think this result is quite interesting and important,” commented Ben Barres of Stanford University in Palo Alto, California, in an e-mail to Alzforum (see full comment below). “They raise the question of what type of reactive astrocyte is induced in Alzheimer’s.” Perhaps, he speculated, the SVZ-derived astrocytes are somehow unavailable to fix damage in the case of AD.—Amber Dance

Comments

  1. I think this result is quite interesting and important. Reactive astrocytosis is a dramatic response of the brain to any injury or disease. But where do these reactive astrocytes come from? Clearly, some local astrocytes alter their gene expression to become reactive, but these new findings indicate that the subventricular zone (SVZ) is an important source of astrocyte progenitors, which secrete THBS4 to activate Notch, which then promotes new astrocyte generation. Moreover, these SVZ cells are critical for repair. I think these findings raise the critical question of whether there are other molecular differences between these two types of reactive astrocytes that are critical for repair—and if so, what are these differences? They also raise the question of what type of reactive astrocyte is induced in Alzheimer's. Perhaps the more reparative type cannot be engaged because the SVZ is somehow not engaged. Much more to do!

    View all comments by Ben Barres

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References

News Citations

  1. After Numb-lessness Wears Off, Brain Reveals Robust Repair Mechanism
  2. Perinatal Soup—Early Pathogen or Toxin Exposures Leave Brain Vulnerable

Paper Citations

  1. Thored P, Arvidsson A, Cacci E, Ahlenius H, Kallur T, Darsalia V, Ekdahl CT, Kokaia Z, Lindvall O. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells. 2006 Mar;24(3):739-47. PubMed.
  2. Kuo CT, Mirzadeh Z, Soriano-Navarro M, Rasin M, Wang D, Shen J, Sestan N, Garcia-Verdugo J, Alvarez-Buylla A, Jan LY, Jan YN. Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche. Cell. 2006 Dec 15;127(6):1253-64. PubMed.
  3. Hochstim C, Deneen B, Lukaszewicz A, Zhou Q, Anderson DJ. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell. 2008 May 2;133(3):510-22. PubMed.
  4. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005 Feb 11;120(3):421-33. PubMed.
  5. Eroglu C, Allen NJ, Susman MW, O'Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, Barres BA. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009 Oct 16;139(2):380-92. PubMed.
  6. Eroglu C. The role of astrocyte-secreted matricellular proteins in central nervous system development and function. J Cell Commun Signal. 2009 Dec;3(3-4):167-76. PubMed.
  7. Adams JC, Lawler J. The thrombospondins. Cold Spring Harb Perspect Biol. 2011 Oct;3(10):a009712. PubMed.
  8. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004 Mar 3;24(9):2143-55. PubMed.

Other Citations

Further Reading

Papers

  1. Li L, Harms KM, Ventura PB, Lagace DC, Eisch AJ, Cunningham LA. Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic. Glia. 2010 Oct;58(13):1610-9. PubMed.
  2. Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM, Doetsch F. A specialized vascular niche for adult neural stem cells. Cell Stem Cell. 2008 Sep 11;3(3):279-88. PubMed.
  3. Leonard BW, Mastroeni D, Grover A, Liu Q, Yang K, Gao M, Wu J, Pootrakul D, van den Berge SA, Hol EM, Rogers J. Subventricular zone neural progenitors from rapid brain autopsies of elderly subjects with and without neurodegenerative disease. J Comp Neurol. 2009 Jul 20;515(3):269-94. PubMed.
  4. Middeldorp J, van den Berge SA, Aronica E, Speijer D, Hol EM. Specific human astrocyte subtype revealed by affinity purified GFAP antibody; unpurified serum cross-reacts with neurofilament-L in Alzheimer. PLoS One. 2009;4(11):e7663. PubMed.

Primary Papers

  1. Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, Warner DS, Liu C, Eroglu C, Kuo CT. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature. 2013 Apr 24; PubMed.

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