Different Functions of Recombinantly Expressed Domains of Tenascin-C in Glial Scar Formation
Authors: Pavle R Andjus
Dunja Bijelić
Mina Perić
Melitta Schachner
Marija Adžić
Igor Jakovčevski
Eckart Förster
Journal: Frontiers in Immunology (2021)
Discipline: IMMUNOLOGY
Keywords: astrocyte; glial scar; microglia/macrophages; spinal cord injury; tenascin-C.
Affiliations: Centre for Laser Microscopy, Faculty of Biology, Institute of Physiology and Biochemistry "Jean Giaja", University of Belgrade, Belgrade, Serbia., Institut für Neuroanatomie und Molekulare Hirnforschung, Ruhr-Universität Bochum, Bochum, Germany., Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.

Abstract:  Extracellular matrix glycoprotein tenascin-C (TnC) is highly expressed in vertebrates during embryonic development and thereafter transiently in tissue niches undergoing extensive remodeling during regeneration after injury. TnC's different functions can be attributed to its multimodular structure represented by distinct domains and alternatively spliced isoforms. Upon central nervous system injury, TnC is upregulated and secreted into the extracellular matrix mainly by astrocytes. The goal of the present study was to elucidate the role of different TnC domains in events that take place after spinal cord injury (SCI). Astrocyte cultures prepared from TnC-deficient (TnC-/-) and wild-type (TnC+/+) mice were scratched and treated with different recombinantly generated TnC fragments. Gap closure, cell proliferation and expression of GFAP and cytokines were determined in these cultures. Gap closure in vitro was found to be delayed by TnC fragments, an effect mainly mediated by decreasing proliferation of astrocytes. The most potent effects were observed with fragments FnD, FnA and their combination. TnC-/- astrocyte cultures exhibited higher GFAP protein and mRNA expression levels, regardless of the type of fragment used for treatment. Application of TnC fragments induced also pro-inflammatory cytokine production by astrocytes in vitro. In vivo, however, the addition of FnD or Fn(D+A) led to a difference between the two genotypes, with higher levels of GFAP expression in TnC+/+ mice. FnD treatment of injured TnC-/- mice increased the density of activated microglia/macrophages in the injury region, while overall cell proliferation in the injury site was not affected. We suggest that altogether these results may explain how the reaction of astrocytes is delayed while their localization is restricted to the border of the injury site to allow microglia/macrophages to form a lesion core during the first stages of glial scar formation, as mediated by TnC and, in particular, the alternatively spliced FnD domain. 

Retracted: No

PubPeer comments:
 Figures 2C and 4C. Much more similar and different than expected. ![file] , 
 2021 erratum. https: academic.oup.com carcin article 42 6 903 6276197 Following publication of this paper it has been brought to the authorsu2019 attention that there appeared to be an error in Figures 2C and 4C. This experiment was performed during 2003, and the authors have been unable to retrieve the original autoradiogram; in addition the person who performed the specific experiment has since retired from science. The p53 protein levels in Figure 2C and Figure 4C represent different patterns. However, the authors agree that there has been an error in figure compilation: the control Tubulin used in Figure 4C does appear to be the same as the control used in Figure 2C. The authors believe this is most likely an innocent mix-up during preparation of the manuscript. As seen in the Figure 4C, treatment with H2O2, does not induce a significant increase in the p53 protein level. This agrees with the conclusion made in the manuscript. The Tubulin presented in Figure 4C has been deleted and the corresponding comment in the legend to Figure 4C has also been deleted in the below version of Figure 4C: These details have been corrected only in this corrigendum erratum to preserve the published version of record. The authors apologize for the error. ,