Laser Lesion in the Mouse Visual Cortex Induces a Stem Cell Niche-Like Extracellular Matrix, Produced by Immature Astrocytes

Abstract

The mammalian central nervous system (CNS) is characterized by a severely limited regeneration capacity. Comparison with lower species like amphibians, which are able to restore even complex tissues after damage, indicates the presence of an inhibitory environment that restricts the cellular response in mammals. In this context, signals provided by the extracellular matrix (ECM) are important regulators of events like cell survival, proliferation, migration, differentiation or neurite outgrowth. Therefore, knowledge of the post-lesional ECM and of cells that produce these factors might support development of new treatment strategies for patients suffering from traumatic brain injury and other types of CNS damage. In the present study, we analyzed the surround of focal infrared laser lesions of the adult mouse visual cortex. This lesion paradigm avoids direct contact with the brain, as the laser beam passes the intact bone. Cell type-specific markers revealed a distinct spatial distribution of different astroglial subtypes in the penumbra after injury. Glial fibrillary acidic protein (GFAP) as marker for reactive astrocytes was found broadly up-regulated, whereas the more immature markers vimentin and nestin were only expressed by a subset of cells. Dividing astrocytes could be identified via the proliferation marker Ki-67. Different ECM molecules, among others the neural stem cell-associated glycoprotein tenascin-C and the DSD-1 chondroitin sulfate epitope, were found on astrocytes in the penumbra. Wisteria floribunda agglutinin (WFA) and aggrecan as markers for perineuronal nets, a specialized ECM limiting synaptic plasticity, appeared normal in the vicinity of the necrotic lesion core. In sum, expression of progenitor markers by astrocyte subpopulations and the identification of proliferating astrocytes in combination with an ECM that contains components typically associated with neural stem/progenitor cells suggest that an immature cell fate is facilitated as response to the injury.

Star power: the emerging role of astrocytes as neuronal partners during cortical plasticity

“…Therefore, based on the immediate drop in (inhibitory) neuronal activity caused by vision loss and subsequent changes in cortical E/I balance ( Figure 1 ), we hypothesize that adult astrocytes undergo (rapid) transcriptome changes, effectively reverting to an immature state, recapitulating aspects of early development which facilitates circuit rewiring. Such a concept is entirely consistent with work performed following CNS injury [ 12 , 13 ], which shows astrocytes adopt an immature phenotype [ 12 , 14 ], concomitant to circuit rewiring [ 12 ].…”

“…This is consistent with live imaging studies demonstrating that brain ECM is highly plastic during development and remodeled in response to local cellular activity [ 18 ]. It is also noteworthy that injury (cortical lesion) reverts astrocytes to a developmentally immature state, with cells expressing ECM components typically associated with neural stem cells/progenitors, suggesting injury response parallels development with ECM modification facilitating circuit rewiring [ 14 ]. This may also be associated with the release of astrocyte-derived factors, such as pentraxin 3, which not only play a role in ECM remodeling but co-operate with proteins, such as thrombospondins, to promote synaptogenesis [ 19 ] (and see Step 4).…”

Loss of the Extracellular Matrix Molecule Tenascin-C Leads to Absence of Reactive Gliosis and Promotes Anti-inflammatory Cytokine Expression in an Autoimmune Glaucoma Mouse Model

“…In regard to the temporal induction, Tnc expression levels were enhanced 3 days post injury and returned to normal levels 7 and 14 days after the induction of brain laser lesion ( 73 ). In the CNS, Tnc is re-expressed under pathological conditions and represents an important component of the glial scar ( 11 , 25 , 36 , 74 – 76 ).…”

Knock-Out of Tenascin-C Ameliorates Ischemia-Induced Rod-Photoreceptor Degeneration and Retinal Dysfunction

“…Enhanced Tnc levels were reported in subarachnoid hemorrhage ( Shiba et al, 2014 ; Suzuki et al, 2020 ), ischemic brain injury ( Manrique-Castano et al, 2020 ) and acute cortical laser lesion ( Roll et al, 2012 ). In the lesioned brain, an increase of relative Tnc expression could only be detected for a short time, while enhanced protein levels were found 3 and 7 days post-lesion, suggesting that high Tnc protein levels exceeded the brief upregulation seen on mRNA level ( Roll et al, 2020 ). Furthermore, a temporally Tnc regulation was observed under retinal degenerative conditions.…”