Chondroitin Sulfate Proteoglycans Revisited: Its Mechanism of Generation and Action for Spinal Cord Injury

Abstract

Reactive astrocytes (RAs) produce chondroitin sulfate proteoglycans (CSPGs) in large quantities after spinal cord injury (SCI) and inhibit axon regeneration through the Rho-associated protein kinase (ROCK) pathway. However, the mechanism of producing CSPGs by RAs and their roles in other aspects are often overlooked. In recent years, novel generation mechanisms and functions of CSPGs have gradually emerged. Extracellular traps (ETs), a new recently discovered phenomenon in SCI, can promote secondary injury. ETs are released by neutrophils and microglia, which activate astrocytes to produce CSPGs after SCI. CSPGs inhibit axon regeneration and play an important role in regulating inflammation as well as cell migration and differentiation; some of these regulations are beneficial. The current review summarized the process of ET-activated RAs to generate CSPGs at the cellular signaling pathway level. Moreover, the roles of CSPGs in inhibiting axon regeneration, regulating inflammation, and regulating cell migration and differentiation were discussed. Finally, based on the above process, novel potential therapeutic targets were proposed to eliminate the adverse effects of CSPGs.

Biomaterials targeting the microenvironment for spinal cord injury repair: progression and perspectives

“…Axon regeneration following SCI is restricted by CSPGs, which are significant extracellular matrix constituents in glial scar tissues. CSPG expression patterns are regulated by phosphate and tension homology deleted on chromosome ten (PTEN) expression in the spinal cord ( Yang et al, 2024 ). In addition, PTEN overexpression causes astrocytes to activate the PI3K/AKT/mTOR pathway, increases the expression of intermediate filament proteins (glial fibrillary acidic protein and vimentin), and reduces the expression of proliferating cell nuclear antigen (PCNA, a proliferation-promoting protein) ( He et al, 2022 ).…”

“…In SCI rats, PTEN overexpression also decreases the expression of CSPGs, inhibits the formation of glial scars, encourages the development of axons, and improves the recovery of nerve function. Thus, glial scar development is mediated by the PI3K/AKT/mTOR signaling pathway ( Yang et al, 2024 ). A common and abundant extracellular matrix protein, fibronectin, is secreted as soluble dimers that form multimeric fibrils on the surface of cells.…”

Advances in Conductive Hydrogel for Spinal Cord Injury Repair and Regeneration

“… 42 In addition, astrocyte proliferation occurs and extracellular matrix molecules such as chondroitin sulfate proteoglycans (CSPGs), fibronectin, laminin, and collagen are deposited by astrocytes in the surrounding lesion area, limiting axonal growth. 43 , 44 It has been shown that certain subtypes of astrocytes yield a neuroprotective effect during the injury process. 45 During the intermediate and chronic phases (2 weeks to 6 months), axonal degeneration continues, and the astroglial scar matures, impeding axonal regeneration and extension.…”