Differential cellular accumulation of connective tissue growth factor defines a subset of reactive astrocytes, invading fibroblasts, and endothelial cells following central nervous system injury in rats and humans
Jm. Schwab et al., Differential cellular accumulation of connective tissue growth factor defines a subset of reactive astrocytes, invading fibroblasts, and endothelial cells following central nervous system injury in rats and humans, J NEUROTRAU, 18(4), 2001, pp. 377-388
In brain injury, the primary trauma is followed by a cascade of cellular an
d molecular mechanisms resulting in secondary injury and scar formation. As
trogliosis and expression of transforming growth factor beta (TGF-beta) are
key components of scar formation. A cytokine mediating the effects of TGF-
beta is connective tissue growth factor (CTGF), a fibrogenic peptide encode
d by an immediate early gene with suggested roles in tissue regeneration an
d aberrant deposition of extracellular matrix. In order to investigate CTGF
in traumatic lesions, we evaluated 20 human brains with traumatic brain in
jury (TBI) and 18 rat brains with stab wound injury. Compared to remote are
as and unaltered control brains, CTGF(+) cells accumulated in border zones
of the traumatic lesion site (p < 0.0001). In the direct peri-lesional rim,
CTGF expression was confined to invading vimentin(+), GFAP(-) fibroblastoi
d cells, endothelial and smooth muscle cells of laminin(+) vessels, and GFA
P(+) reactive astrocytes. In the direct peri-lesional rim, CTGF(+) astrocyt
es (>80%) co-expressed the activation associated intermediate filaments nes
tin and vimentin. In injured rat brains, numbers of CTGF(+) cells peaked at
day 3 and 7 and decreased to almost base level 3 weeks postinjury, whereas
in humans, CTGF(+) cells remained persistently elevated up to 6 months (p
< 0.0001). The restricted accumulation of CTGF(+)-reactive astrocytes and C
TGF(+) fibroblastoid cells lining the adjacent laminin(+) basal lamina sugg
ests participation of these cells in scar formation. Furthermore, peri-lesi
onal upregulation of endothelial CTGF expression points to a role in blood-
brain barrier function and angiogenesis. In addition, CTGF appears to be a
sensitive marker of early astrocyte activation.