Matrix remodeling after stroke. De novo expression of matrix proteins and integrin receptors.

Following an ischemic insult to the central nervous system a reorganization of cells and tissue takes place as the surrounding cells attempt to limit the injury, repair the damage, and restore normal architecture of the brain. This tissue remodeling requires de novo synthesis of genes and proteins which enables cells to actively change their relationship with the existing extracellular matrix and with other cells to reorganize the damaged tissue. We have identified two key molecular components of the matrix remodeling process after focal ischemia: osteopontin (OPN) and its integrin receptor alpha v beta 3 (alpha v beta 3). OPN is initially expressed by activated macrophages and microglia in the periinfarct region (24-48 hr) and at later times (5-15 days) in the core infarct. After focal stroke the alpha v beta 3 was upregulated by astrocytes in the periinfarct region. Spatial and temporal analyses demonstrated that at 5 days after injury the alpha v beta 3-positive astrocytes were at a distance from the osteopontin-expressing macrophages; by 15 days the alpha v beta 3-expressing astrocytes were localized within an osteopontin-rich matrix. In vitro OPN was shown to induce migration of astrocytes in a Boyden chamber system. These data suggest that OPN derived from microglia at the infarct border zone (and possible macrophages in the infarct core) may serve as an "astrokine" (suggested term for astrocyte chemoattractant) to organize the astrocyte scar after focal stroke. Our data demonstrate profound changes in brain matrix remodeling after focal ischemic stroke, including the synthesis and release of matrix proteins alien to the normal brain, the expression of integrin receptors that ligate these proteins, and possibly a novel function for microglial-derived OPN in astrocyte migration after focal ischemia that may drive glial activation, organization, and repair functions.