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.
Highlights
Spinal cord injury (SCI) is a severe neurological disorder with a limited hope for recovery, presenting a health care and socioeconomic problem
A scratch wound assay was performed in TnC+/+ and TnC-/cortical astrocyte cultures to measure the response to mechanical injury [30]
It is worth mentioning that mechanical stretching of an astrocyte monolayer is not the most adequate model for assaying glial scar formation since it lacks many components of in vivo injury [35]
Summary
Spinal cord injury (SCI) is a severe neurological disorder with a limited hope for recovery, presenting a health care and socioeconomic problem. SCI is a two-step process, primary mechanical injury is followed by secondary inflammation and apoptosis through which existing injury spreads further into the surrounding tissue [1]. The hallmark of these events is the formation of the glial scar with two distinct parts. A majority of cellular functions, signal transduction, and tissue homeostasis are maintained by extracellular matrix components (ECM) making the ECM an interesting target for modulation of the outcome of injury. It is noteworthy in this context that the ECM glycoprotein tenascin-C (TnC) is strongly upregulated after injury of central nervous system [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
