Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in diverse homeostatic and pathological processes. Several MMPs are expressed within the CNS and serve important normal and pathological functions during development and adulthood. An early and major pathological effect of MMP activity after cerebral ischemia is opening of the blood-brain barrier (BBB). More recent work demonstrates emerging roles for MMPs and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), in the regulation of neuronal cell death. In addition, MMPs and TIMPs are likely to play important roles during the repair phases of cerebral ischemia, particularly during angiogenesis and reestablishment of cerebral blood flow. This review attempts to elucidate how MMPs and TIMPs may provide detrimental or beneficial actions during the injury and repair processes after cerebral ischemia. These processes will have important implications for therapies using MMP inhibitors in stroke.

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STEM CELLS 2008;26:3139 -3149 Disclosure of potential conflicts of interest is found at the end of this article.

Vascular cells provide a neural stem/progenitor cell (NSPC) niche that regulates expansion and differentiation of NSPCs within the germinal zones of the embryonic and adult brain under both physiologic and pathologic conditions. Here, we examined the NSPC-endothelial cell (NSPC/EC) interaction under conditions of ischemia, both in vitro and after intracerebral transplantation. In culture, embryonic mouse NSPCs supported capillary morphogenesis and protected ECs from cell death induced by serum starvation or by transient oxygen and glucose deprivation (OGD). Neural stem/progenitor cells constitutively expressed hypoxia-inducible factor 1alpha (HIF-1alpha) transcription factor and vascular endothelial growth factor (VEGF), both of which were increased approximately twofold after the exposure of NSPCs to OGD. The protective effects of NSPCs on ECs under conditions of serum starvation and hypoxia were blocked by pharmacological inhibitors of VEGF signaling, SU1498 and Flt-1-Fc. After intracerebral transplantation, NSPCs continued to express HIF-1alpha and VEGF, and promoted microvascular density after focal ischemia. These studies support a role for NSPCs in stabilization of vasculature during ischemia, mediated via HIF-1alpha-VEGF signaling pathways, and suggest therapeutic application of NSPCs to promote revascularization and repair after brain injury.

The purpose of this study was to ascertain the relative contribution of neural stem/progenitor cells (NSPCs) of the subventricular zone (SVZ) to lineages that repopulate the injured striatum following focal ischemia. We utilized a tamoxifen-inducible Cre/loxP system under control of the nestin promoter, which provides permanent YFP labeling of multipotent nestin + SVZ-NSPCs prior to ischemic injury and continued YFP expression in all subsequent progeny following stroke. YFP reporter expression was induced in adult male nestin-CreER T2 :R26R-YFP mice by tamoxifen administration (180 mg/kg, daily for 5 days). Fourteen days later, mice were subjected to 60 minute transient middle cerebral artery occlusion (MCAO) and sacrificed at 2 days, 2 weeks or 6 weeks post-MCAO for phenotypic fate mapping of YFP + cells using lineage-specific markers. Migration of YFP + cells from SVZ into the injured striatal parenchyma was apparent at 2 and 6 weeks, but not 2 days, post-MCAO. At 2 weeks post-MCAO, the average percent distribution of YFP + cells within the injured striatal parenchyma was as follows: 10% Dcx + neuroblasts, 15-20% oligodendrocyte progenitors, 59% GFAP + astrocytes, and only rare NeuN + postmitotic neurons. A similar phenotypic distribution was observed at 6 weeks, except for an increased average percentage of YFP + cells that expressed Dcx + (20%) or NeuN (5%). YFP + cells did not express endothelial markers, but displayed unique anatomical relationships with striatal vasculature. These ** Corresponding Author: Lee Anna Cunningham, PhD, Department of Neurosciences, University of New Mexico Health Sciences Center, MSC08 4740, 1 University of New Mexico, Albuquerque, leeanna@salud.unm.edu, NIH Public Access Author ManuscriptGlia. Author manuscript; available in PMC 2011 October 1.

Bone marrow-derived cells (BMDCs) contribute to revascularization after ischemia. However, the mechanisms by which BMDCs support vessel remodeling after cerebral ischemia are not clear. Using mouse chimeras that express enhanced green fluorescent protein in reconstituted bone marrow, we investigated the role of BMDCs in revascularization and brain repair after middle cerebral artery occlusion of murine brain. After ischemia, two populations of BMDCs were observed, one in the brain parenchyma and another associated with the vasculature. The number of BMDCs that infiltrated the brain parenchyma peaked at 7 days and persisted through 14 days, the last time point observed. The majority of BMDCs were characterized as microglia, based on cell-type-specific marker expression. We observed a robust angiogenic response after cerebral ischemia. Bone marrow-derived cells associated with remodeling blood vessels were negative for endothelial markers, but were surrounded by basal lamina and expressed desmin and vimentin, identifying these cells as pericytes. Quantification of BMDCs that expressed desmin revealed increasing desmin expression with time. Perivascular associated BMDCs that expressed desmin were immunoreactive for the angiogenic factors vascular endothelial growth factor and transforming growth factor-b. These findings suggest that pericytes are recruited from the periphery and are involved in blood vessel stabilization during ischemia-induced angiogenesis.

These observations indicate that moderate FAE results in a long-term, persistent defect in neurogenic responses to behavioral challenge.

Metalloproteinase activity at the cell surface influences cellular sensitivity to extrinsic death vs. survival signals in a variety of cell types, through proteolytic shedding of cell surface signalling molecules. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a unique natural metalloproteinase inhibitor that plays a pro-apoptotic role through its ability to inhibit metalloproteinases that proteolytically cleave death receptors and their ligands from the cell surface. To study the convergence of metalloproteinase activity and death receptor signalling in neurons, we established an in vitro model of neuronal apoptosis utilizing the chemotherapeutic drug, doxorubicin (Dox). Primary cultures established from embryonic rat cerebral cortices displayed robust and selective neuronal apoptosis in response to Dox, an effect that was dependent on the activation of the death receptor, Fas. We demonstrate that both TIMP-3 and matrix metalloproteinase-3 (MMP-3) are constitutively expressed by primary cortical neurons in culture, and selectively modulated Fas-mediated neuronal apoptosis induced by Dox. Metalloproteinase inhibition by TIMP-3 was found to be necessary for Dox-induced neuronal death, whereas addition of active MMP-3 markedly attenuated apoptosis and diminished Fas-Fas ligand interaction at the cell surface. These observations implicate a physiological role for the balance of TIMP-3 and MMP-3 activity at the neuronal surface in regulating death receptor sensitivity. The convergence of metalloproteinase activity and death receptor signalling at the cell surface may influence neuronal cell death vs. survival decisions.