Expression of Transforming Growth Factor-β Receptors in Meningeal Fibroblasts of the Injured Mouse Brain

Abstract

The fibrotic scar which is formed after traumatic damage of the central nervous system (CNS) is considered as a major impediment for axonal regeneration. In the process of the fibrotic scar formation, meningeal fibroblasts invade and proliferate in the lesion site to secrete extracellular matrix proteins, such as collagen and laminin. Thereafter, end feet of reactive astrocytes elaborate a glia limitans surrounding the fibrotic scar. Transforming growth factor-beta1 (TGF-beta1), a potent scar-inducing factor, which is upregulated after CNS injury, has been implicated in the formation of the fibrotic scar and glia limitans. In the present study, expression of receptors to TGF-beta1 was examined by in situ hybridization histochemistry in transcortical knife lesions of the striatum in the mouse brain in combination with immunofluorescent staining for fibroblasts and astrocytes. Type I and type II TGF-beta receptor mRNAs were barely detected in the intact brain and first found in meningeal cells near the lesion 1 day postinjury. Many cells expressing TGF-beta receptors were found around the lesion site 3 days postinjury, and some of them were immunoreactive for fibronectin. After 5 days postinjury, many fibroblasts migrated from the meninges to the lesion site formed the fibrotic scar, and most of them expressed TGF-beta receptors. In contrast, few of reactive astrocytes expressed the receptors throughout the postinjury period examined. These results indicate that meningeal fibroblasts not reactive astrocytes are a major target of TGF-beta1 that is upregulated after CNS injury.

Roles of Chondroitin Sulfate and Dermatan Sulfate in the Formation of a Lesion Scar and Axonal Regeneration after Traumatic Injury of the Mouse Brain

“…24 The present in vitro experiment demonstrates that addition of ChABC or ChB inhibited the effect of TGF-b1 on cluster formation in the coculture (Fig. 5).…”

“…2C) that expresses TGF-b receptors 24 DS immunoreactivity is also localized in the TGF-b1-induced cluster FIG. 6.…”

Transforming Growth Factor Beta in the Central Nervous System

“…However, considerable differences between the distribution of mRNAs and immunoreactivities of TGF-βs have also been reported. Most importantly, TGF-β1 immunoreactivity was reported to be constitutively present only in meninges and the choroid plexus in the brain (Komuta et al, 2009 ;Unsicker et al, 1991) while a more widespread expression of the mRNA of this isoform was described including intense labeling in some cortical and hippocampal cells, the medial preoptic area, the paraventricular hypothalamic nucleus, the central amygdaloid nucleus, and the superior olive. Furthermore, TGF-β2 and β3 immunoreactivities entirely overlapped and, in general, were found in large multipolar neurons with the level of TGF-ß2 being considerably higher (Bottner et al, 2000).…”

Scar-modulating treatments for central nervous system injury

“…Local injection of α,α'-dipyridyl, both an iron chelator and an inhibitor of collagen triple helix synthesis, signifi cantly reduces collagen formation, and thus suppresses the formation of fi brotic scars [48][49][50] . The expression of TGF-β1 and its receptors (types I and II) increases during the migration of fibroblasts to the injury site, and the increased TGF-β1 directly activates meningeal fibroblasts [50] .…”

“…The expression of TGF-β1 and its receptors (types I and II) increases during the migration of fibroblasts to the injury site, and the increased TGF-β1 directly activates meningeal fibroblasts [50] . Accordingly, fibrotic scar formation is promoted by exogenous TGF-β1…”