Analyzing the role of extracellular matrix during nervous system development to advance new regenerative strategies

Regeneration in the central nervous system (CNS) is limited, and CNS damage often leads to cognitive impairment or permanent functional motor and sensory loss. Impaired regenerative capacity is multifactorial and includes inflammation, loss of the bloodbrain barrier, and alteration in the extracellular matrix (ECM). One of the main problems is the formation of a glial scar and the production of inhibitory ECM, such as proteoglycans, that generates a physical and mechanical barrier, impeding axonal regrowth (Figure 1A). However, in vivo studies of axons from injured spinal cords reveal that they initially enter an acute fragmentation period following lesion formation, which is followed by proximal axonal end regrowth over several weeks. At this point, it is possible to see the axonal tip advancing and branching with an erratic growth pattern (Kerschensteiner et al., 2005). The authors conclude that the impaired reinnervation is due not only to the presence of inhibitory ECM, but also to the absence of directional guiding to the synaptic counterpart. Similar axonal misguidance occurs during optic nerve regeneration, where injured axons can grow in the presence of neurotrophic factors, including ciliary neurotrophic factor (CNTF), although they follow irregular pathways (Pernet and Schwab, 2014). More promising strategies to improve CNS regeneration include the combination of several approaches, such as reducing the inflammatory processes generated in response to the injury, addition of growth factors, incorporation of stem cells, and modification of the ECM. One of the approaches to induce matrix remodeling is to neutralize the intrinsic inhibitory matrix (e.g., enzymatic digestion of proteoglycans with chondroitinase ABC) and generate a permissive matrix where the axons can grow. With recent rapid advances in nanotechnology, the use of tissue-engineered scaffolds has allowed some advances in the reconstruction of injured tissues and reconnection of neuronal processes. These matrices are based on particular ECM molecules (e.g., laminin) as well as natural or synthetic polymers (e.g., chitosan or polyhydroxy acids) and decellularized tissue (review in Ricks et al., 2014).