Role of the lesion scar in the response to damage and repair of the central nervous system

Abstract

Traumatic damage to the central nervous system (CNS) destroys the blood-brain barrier (BBB) and provokes the invasion of hematogenous cells into the neural tissue. Invading leukocytes, macrophages and lymphocytes secrete various cytokines that induce an inflammatory reaction in the injured CNS and result in local neural degeneration, formation of a cystic cavity and activation of glial cells around the lesion site. As a consequence of these processes, two types of scarring tissue are formed in the lesion site. One is a glial scar that consists in reactive astrocytes, reactive microglia and glial precursor cells. The other is a fibrotic scar formed by fibroblasts, which have invaded the lesion site from adjacent meningeal and perivascular cells. At the interface, the reactive astrocytes and the fibroblasts interact to form an organized tissue, the glia limitans. The astrocytic reaction has a protective role by reconstituting the BBB, preventing neuronal degeneration and limiting the spread of damage. While much attention has been paid to the inhibitory effects of the astrocytic component of the scars on axon regeneration, this review will cover a number of recent studies in which manipulations of the fibroblastic component of the scar by reagents, such as blockers of collagen synthesis have been found to be beneficial for axon regeneration. To what extent these changes in the fibroblasts act via subsequent downstream actions on the astrocytes remains for future investigation.

Fig. 1

Schematic drawings represent the process of the lesion scar formation in the mouse brain. One day after traumatic CNS injury, the BBB is disrupted and macrophages infiltrated the BBB-free area. a Upregulation of GFAP immunoreactivity in reactive astrocytes is already observed. b Three days after the injury, reactive astrocytes significantly increase around the lesion site, but they are absent from the lesion center where the BBB is destroyed. Fibroblasts intrude from the damaged meninges to the lesion site. c By 1 week after injury, fibroblasts actively proliferate and secrete ECMs to form the fibrotic scar. Reactive astrocytes re-occupy the surrounding area of the lesion site and BBB-free area around the lesion site is eliminated. d At 2 weeks after, processes of reactive astrocytes seal the lesion site to form a glia limitans

Fig. 2

Elimination of the fibrotic scar in the mouse and rat brain has been shown to promote axonal regeneration in a variety of animal models. a In injured brain, axons stop at the border of the fibrotic scar and do not regenerate. b In neonatal and DPY-treated animals, axons regenerate despite of the presence of glial scar and chondroitin sulfate proteoglycan (CSPG) (Stichel et al. ; Kawano et al. 2005). c In the hypothalamic arcuate nucleus (ARC) and by chondroitinase ABC (ChABC) treatment, upregulation of chondroitin sulfate is prevented and axons regenerate (Homma et al. ; Li et al. 2007). d In olfactory ensheathing cell (OEC)-transplanted rats, fibrotic scar is not formed and axons regenerate (Teng et al. 2008)

Fig. 3

Role of TGF-β on the formation of fibrotic scar which inhibits axonal regeneration. a Schematic drawing of the transection of mouse brain (Kawano et al. 2005). Ascending dopaminergic axons which arise from the substantia nigra and ventral tegmental area project to the telencephalic structures are cut at the proximal part of the striatum (green line) with a knife of 2 mm width. b The fibrotic scar containing dense Type IV collagen (Col IV) deposits (red) is formed in the lesion site 2 weeks after injury and transected tyrosine hydroxylase (TH)-immunoreactive dopamine (DA) axons (green) stop at the fibrotic scar. c Continuous injection of the inhibitor of TGF-β, LY-364947 into the lesion site completely suppresses the fibrotic scar formation and promotes axonal regeneration (Yoshioka et al. 2011). d–k In vitro model of the lesion scar (Kimura-Kuroda et al. 2010). d–g Meningeal fibroblasts (magenta) and cerebral astrocytes (green) form separate colonies in coculture. Cerebellar neurons grow better on astoricytes than on fibroblasts. h–k When TGF-β1 is added to the coculture, cells aggregate to form a fibrotic scar-like cluster which repels neurites of cerebellar neurons (blue). Scale bars (b, c) 200 μm, (d–k) 100 μm