The Composition and Cellular Sources of CSPGs in the Glial Scar After Spinal Cord Injury in the Lamprey

Abstract

Axon regrowth after spinal cord injury (SCI) is inhibited by several types of inhibitory extracellular molecules in the central nervous system (CNS), including chondroitin sulfate proteoglycans (CSPGs), which also are components of perineuronal nets (PNNs). The axons of lampreys regenerate following SCI, even though their spinal cords contain CSPGs, and their neurons are enwrapped by PNNs. Previously, we showed that by 2 weeks after spinal cord transection in the lamprey, expression of CSPGs increased in the lesion site, and thereafter, decreased to pre-injury levels by 10 weeks. Enzymatic digestion of CSPGs in the lesion site with chondroitinase ABC (ChABC) enhanced axonal regeneration after SCI and reduced retrograde neuronal death. Lecticans (aggrecan, versican, neurocan, and brevican) are the major CSPG family in the CNS. Previously, we cloned a cDNA fragment that lies in the most conserved link-domain of the lamprey lecticans and found that lectican mRNAs are expressed widely in lamprey glia and neurons. Because of the lack of strict one-to-one orthology with the jawed vertebrate lecticans, the four lamprey lecticans were named simply A, B, C, and D. Using probes that distinguish these four lecticans, we now show that they all are expressed in glia and neurons but at different levels. Expression levels are relatively high in embryonic and early larval stages, gradually decrease, and are upregulated again in adults. Reductions of lecticans B and D are greater than those of A and C. Levels of mRNAs for lecticans B and D increased dramatically after SCI. Lectican D remained upregulated for at least 10 weeks. Multiple cells, including glia, neurons, ependymal cells and microglia/macrophages, expressed lectican mRNAs in the peripheral zone and lesion center after SCI. Thus, as in mammals, lamprey lecticans may be involved in axon guidance and neuroplasticity early in development. Moreover, neurons, glia, ependymal cells, and microglia/macrophages, are responsible for the increase in CSPGs during the formation of the glial scar after SCI.

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

“…The CSPGs that make up PNNs can be secreted by various cells, including neurons, microglia, astrocytes, etc. [ 15 , 43 , 44 ]. Among the subtypes of astrocytes, the CSPGs are secreted primarily by non-proliferative RAs located in spared but reactive neural tissue because they are not detected at the site of injury, where proliferating RAs are abundant.…”

“…There are several types of CSPGs, including CSPG1 (Aggrecan), CSPG2 (Versican), CSPG3 (Neurocan), CSPG4 (NG2), CSPG7 (Brevican), etc. [ 15 ]. Among them, Aggrecan, Versican, Neurocan, and Brevican belong to the lectican family and form perineuronal nets (PNNs), which inhibit axon regeneration [ 2 , 16 ].…”

Electroacupuncture promotes the repair of the damaged spinal cord in mice by mediating neurocan‐perineuronal net

“…Researchers have recently focused on PNN's role in cortical plasticity, neural activity regulation, neural circuits functional reconstruction, and neurodegenerative diseases 6,10–12 . A number of studies have shown that chondroitin sulfate ABC (ChABC), a drug targeting core protein saccharides of PNNs, effectively treats SCI 13–15 . Therefore, modulating PNN is a potentially promising treatment strategy for SCI.…”

“… 6 , 10 , 11 , 12 A number of studies have shown that chondroitin sulfate ABC (ChABC), a drug targeting core protein saccharides of PNNs, effectively treats SCI. 13 , 14 , 15 Therefore, modulating PNN is a potentially promising treatment strategy for SCI. However, the specific mechanism of PNN in spinal cord injury remains unclear and needs to be further explored and studied.…”