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Neonatal Astrocyte-derived Factor Boosts NSC-mediated Repair after Traumatic Brain Injury

Review of “Effects and mechanism of action of neonatal versus adult astrocytes on neural stem cell proliferation after traumatic brain injury” from STEM CELLS by Stuart P. Atkinson

Researchers from Nantong University (Nantong, China) recently sought to discover more about the mobilization and activation of neural stem cells (NSCs) as a regenerative response to traumatic brain injury (TBI) [1, 2]. Studies have demonstrated elevated levels of neurogenesis in neonates when compared with adults [3-5], and Dai et al. assessed a role for factors secreted from astrocytes in their new STEM CELLS study in the knowledge that the ability of NSCs to proliferate and differentiate depends on the neural microenvironment [6]. Fascinatingly, the authors now report that neonatal astrocytes, which provide nutrition, support, and protection to neurons, have a heightened ability to increase NSC proliferation and TBI repair when compared to adult astrocytes thanks, in part, to the elevated expression of Tenascin‐C (TNC).

The authors first isolated primary astrocytes from rats one day (neonatal) or eight weeks (adult) after birth and then generated astrocyte-conditioned medium (CM). While the addition of neonatal astrocyte CM prompted the proliferation of NSCs, adult astrocyte CM did not (regardless of their inflammatory status), prompting the authors to analyze the content of the two different CMs to understand the growth factors involved. 

Fascinatingly, proteomic analysis using liquid chromatography with tandem mass spectrometry highlighted a potential role for Tenascin‐C (TNC), a glycoprotein expressed in restricted neurogenic areas of the central nervous system, in NSC proliferation, given its presence at high levels in neonatal astrocyte CM and its absence from adult astrocyte CM. Additionally, immunofluorescence analysis confirmed the presence of high levels of TNC in the cerebral cortex of neonatal rats and lower levels in the same region in adult rats. 

In vitro analyses provided evidence that recombinant TNC binds to the epidermal growth factor receptor (EGFR) present on NSCs where it activates the PI3K‐AKT pathway to promote proliferation. Subsequent in vivo evaluations suggested that the injection of TNC recombinant protein or TNC-overexpressing lentivirus in adult rats induced damage repair in a rat model of TBI through the increased proliferation of NSCs and increasing the number of newborn immature neurons differentiated from NSCs.

Overall, the authors provide both a mechanistic understanding of why neonates tend to exhibit better neuroregenerative abilities than adults, due to the activity of neonatal astrocytes, and a potential future therapeutic target for injury repair after TBI, in TNC.

For more on NSC-mediated repair after traumatic brain injury and the role of astrocyte-secreted factors, stay tuned to the Stem Cells Portal

References

  1. Buffo A, Rite I, Tripathi P, et al., Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proceedings of the National Academy of Sciences 2008;105:3581.
  2. Ahmed AI, Shtaya AB, Zaben MJ, et al., Endogenous GFAP-Positive Neural Stem/Progenitor Cells in the Postnatal Mouse Cortex Are Activated following Traumatic Brain Injury. Journal of Neurotrauma 2011;29:828-842.
  3. Shetty AK and Hattiangady B, Postnatal age governs the extent of differentiation of hippocampal CA1 and CA3 subfield neural stem/progenitor cells into neurons and oligodendrocytes. International Journal of Developmental Neuroscience 2013;31:646-656.
  4. Encinas Juan M, Michurina Tatyana V, Peunova N, et al., Division-Coupled Astrocytic Differentiation and Age-Related Depletion of Neural Stem Cells in the Adult Hippocampus. Cell Stem Cell 2011;8:566-579.
  5. Gu J, Bao Y, Chen J, et al., The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs. Frontiers in Cellular Neuroscience 2016;10:282.
  6. Temple S, The development of neural stem cells. Nature 2001;414:112-117.