Filling the Gaps – A Call for Comprehensive Analysis of Extracellular Matrix of the Glial Scar in Region- and Injury-Specific Contexts

Abstract

Central nervous system (CNS) injury results in chronic scar formation that interferes with function and inhibits repair. Extracellular matrix (ECM) is prominent in the scar and potently regulates cell behavior. However, comprehensive information about the ECM proteome is largely lacking, and region-as well as injury-specific differences are often not taken into account. These aspects are the focus of our perspective on injury and scar formation. To highlight the importance of such comprehensive proteome analysis we include data obtained with novel analysis tools of the ECM composition in the scar and show the contribution of monocytes to the ECM composition after traumatic brain injury (TBI). Monocyte invasion was reduced using the CCR2-/-mouse line and stepwise de-cellularization and proteomics allowed determining monocyte-dependent ECM composition and architecture of the glial scar. We find significant reduction in the ECM proteins Tgm1, Itih (1,2, and 3), and Ftl in the absence of monocyte invasion. We also describe the scar ECM comprising zones with distinctive composition and show a subacute signature upon comparison to proteome obtained at earlier times after TBI. These results are discussed in light of injury-, region-and time-specific regulation of scar formation highlighting the urgent need to differentiate injury conditions and CNS-regions using comprehensive ECM analysis.

Repetitive injury and absence of monocytes promote astrocyte self‐renewal and neurological recovery

“…Accordingly, an injury-induced accumulation of astrocytes in vicinity of BVs is crucial for preventing secondary injury following TBI and may directly affect neuronal function and survival in the injury site (Robel & Sontheimer, 2016). This suggestion is further supported by the reduction of the NeuN-free area and an alleviated loss of synapses persisting in the injury site of CCR2 −/− mice at the subacute phase after injury (Frik et al, 2018;Kjell & Gotz, 2020).…”

“…These were factors of WNT, EGF, insulin/IGF and interleukin 3 signaling that have been implicated in regulating glial cell proliferation after injury (Dimou & Gotz, 2014;Gotz, Sirko, Beckers, & Irmler, 2015;Robel, Berninger, & Gotz, 2011). Furthermore, the absence of invading monocytes elicits not only the multiple effects on pathways regulating astrocyte proliferation at the lesion site, but also strongly affects ECM formation during acute and subacute stages after lesion (Frik et al, 2018;Kjell & Gotz, 2020). Given that many growth factors involved in the proliferative response at the injury site (e.g., VEGF,PDGF, interact with the ECM (Brizzi, Tarone, & Defilippi, 2012;R.…”

“…One such mechanism is the invasion of monocytes, as their absence promoted proliferation of self-renewing versus newly recruited astrocytes. Indeed, many growth factors and extracellular matrix (ECM) factors are substantially altered after TBI in CCR2 −/− mice (Frik et al, 2018;Kjell & Gotz, 2020) and could hence contribute to promote reactive astrocyte self-renewal. These were factors of…”

“…Given that many growth factors involved in the proliferative response at the injury site (e.g., FGF-2, VEGF, PDGF, TGF-β1) interact with the ECM (Brizzi, Tarone, & Defilippi, 2012;R. A. Clark, 2008;Hynes, 2009;Roll & Faissner, 2014), ECM changes observed in the injury site of the CCR2 −/− mice (Frik et al, 2018;Kjell & Gotz, 2020) may modify the local concentration and/or ability of these factors to bind to their receptors, allowing a plethora of cell surface signaling pathways to influence astrocyte proliferation. Thus, monocyte invasion following TBI triggers many extrinsic factors promoting recruitment of new astrocytes into proliferation.…”

Time-Course Changes of Extracellular Matrix Encoding Genes Expression Level in the Spinal Cord Following Contusion Injury—A Data-Driven Approach

“…All components of the neural ECM (interstitial, perineuronal, basement membrane) are recognized as players in SCI evolution, repair attempts and therefore in functional outcome in chronic lesions [ 12 ]. Most published reports, however, describe ECM variations at the core of the lesion, focusing on scar formation [ 20 ] and to the best of our knowledge, no data is available on the surrounding segments, where the ascending (caudal segment) and descending (rostral segment) nerve pathways reside and where a bridge between the pathological microenvironment of the scar and intact tissue is likely to take place [ 5 , 12 ]. In these areas, active neurons, reactive glia, including astrocytes, microglia and NG2-OPCs are present and play a possible role in ECM modification [ 21 ].…”