Inhibition of matrix metalloproteinase-9 attenuated neural progenitor cell migration after photothrombotic ischemia

Kang, Seong Su; Kook, Ji Hyun; Hwang, Shinae; Park, Sah Hoon; Nam, Sang Chae; Kim, Jong Keun

doi:10.1016/j.brainres.2008.06.056

Cited by 38 publications

(26 citation statements)

References 39 publications

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“…C57 NSCs were also found to exhibit a blunted migratory responsiveness to SDF-1 (known to mediate neural progenitor cell motility after ischemia 56 ) and decreased induction of MMP-9 (known to be involved in modulating neuroblast migration from the SVZ after stroke and ischemia 57,58 ) compared with CD-1 NSCs. This finding is consistent with our hypothesis that the behavioral data exhibited by the C57 pups may be a consequence of their relative lower proliferative and migratory rates and higher susceptibility to undergo apoptosis in response to a reduction in O 2 % because of their relatively blunted HIF-1␣ response compared with that of CD-1 pups and in part mediated by their blunted response to SDF-1.…”

Section: Discussionmentioning

confidence: 95%

Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal

Liu

Michaud

et al. 2009

The American Journal of Pathology

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Premature infants have chronic hypoxia, resulting in cognitive and motor neurodevelopmental handicaps caused by suboptimal neural stem cell (NSC) repair/ recovery in neurogenic zones (including the subventricular and the subgranular zones). Understanding the variable central nervous system repair response is crucial to identifying "at risk" infants and to increasing survival and clinical improvement of affected infants. Using mouse strains found to span the range of responsiveness to chronic hypoxia, we correlated differential NSC survival and self-renewal with differences in behavior. We found that C57BL/6 (C57) pups displayed increased hyperactivity after hypoxic insult; CD-1 NSCs exhibited increased hypoxia-induced factor 1␣ (HIF-1␣) mRNA and protein, increased HIF-1␣, and decreased prolyl hydroxylase domain 2 in nuclear fractions, which denotes increased transcription/translation and decreased degradation of HIF-1␣. C57 NSCs exhibited blunted stromal-derived factor 1-induced migratory responsiveness, decreased matrix metalloproteinase-9 activity, and increased neuronal differentiation. Adult C57 mice exposed to hypoxia from P3 to P11 exhibited learning impairment and increased anxiety. These findings support the concept that behavioral differences between C57 and CD-1 mice are a consequence of differential responsiveness to hypoxic insult, leading to differences in HIF-1␣ signaling and resulting in lower NSC proliferative/migratory and higher apoptosis rates in C57 mice. Information gained from these studies will aid in design and effective use of preventive therapies in the very low birth weight infant population. Preterm birth is known to result in cognitive and motor disabilities and recent evidence suggests that there can be significant recovery over time in some patients.

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Section: Discussionmentioning

confidence: 95%

Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal

Liu

Michaud

et al. 2009

The American Journal of Pathology

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“…Enzymatic degradation of chondroitin sulfate expressed by proteoglycans in the stem cell niche promotes differentiation and migration of neural progenitor cells (Gu et al, 2009), indicating an influence of these extracellular matrix molecules on neurogenesis. The importance of the extracellular matrix in regulating neurogenesis has been supported by studies on matrix metalloproteinases, which can regulate neurogenesis by proteolytic modulation of extracellular matrix molecules (Bovetti et al, 2007;Kang et al, 2008;Tonti et al, 2009;Zhang et al, 2007). Deficiency in tenascin-R affects developmental neurogenesis in the mouse olfactory bulb, but not neurogenesis in the adult, thus highlighting that regulation of neurogenesis can vary during an animal's lifetime (David et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

Xu¹,

Xiao²,

Jakovčevski³

et al. 2014

Development

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Abnormal generation of inhibitory neurons that synthesize c-aminobutyric acid (GABAergic) is characteristic of neuropsychological disorders. We provide evidence that the extracellular matrix molecule tenascin-R (TNR) -which is predominantly expressed by a subpopulation of interneuronsplays a role in the generation of GABAergic and granule neurons in the murine dentate gyrus by regulating fate determination of neural stem or progenitor cells (NSCs). During development, absence of TNR in constitutively TNR-deficient (TNR 2/2 ) mice results in increased numbers of dentate gyrus GABAergic neurons, decreased expression of its receptor b1 integrin, increased activation of p38 MAPK and increased expression of the GABAergic specification gene Ascl1. Postnatally, increased GABAergic input to adult hippocampal NSCs in TNR 2/2 mice is associated not only with increased numbers of GABAergic and, particularly, parvalbumin-immunoreactive neurons, as seen during development, but also with increased numbers of granule neurons, thus contributing to the increased differentiation of NSCs into granule cells. These findings indicate the importance of TNR in the regulation of hippocampal neurogenesis and suggest that TNR acts through distinct direct and indirect mechanisms during development and in the adult.

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“…This finding suggests that it is a threshold of MMP-9 expression/activity that is critical for altered cell migration and proliferation. Although to our knowledge this is the first time that MMP-9 activity has been linked to NSC proliferation, MMP-9 has been shown to influence NSC migration (65)(66)(67) and differentiation (67) in vitro and to play a role in the response of NSCs in vivo after injury (67) or stroke/hypoxia (65,66,68). Moreover, MMP-9 is found in a number of areas of the brain, including neurogenic niches (69), and thus is likely to influence stem cell proliferation and migration in vivo.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase (MMP)-9 Induced by Wnt Signaling Increases the Proliferation and Migration of Embryonic Neural Stem Cells at Low O2 Levels

Ingraham

Park

Makarenkova

et al. 2011

Journal of Biological Chemistry

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Recent studies have shown that various neural and embryonic stem cells cultured in 1-8% oxygen (O 2 ), levels lower than those typically used in cell culture (20.9%), displayed increased rates of proliferation; however, the molecular mechanisms underlying these changes are largely undefined. In this study, using rigorously controlled O 2 levels, we found that neural stem cells (NSCs) from embryonic day 15 rat cortex increased their rate of proliferation and migration in 1% O 2 relative to 20% O 2 without changes in viability. We sought to identify molecular changes in NSCs grown in 1% O 2 that might account for these increases. In 1% O 2 , levels of the hypoxia-inducible transcription factor HIF-1␣ were transiently increased. Reduced adherence of NSCs in 1% O 2 to basement membrane-coated plates was observed, and quantitative RT-PCR analysis confirmed that the levels of mRNA for an assortment of cell adhesion and extracellular matrix molecules were altered. Most notable was a 5-fold increase in matrix metalloproteinase (MMP)-9 mRNA. Specific inhibition of MMP-9 activity, verified using a fluorescent substrate assay, prevented the increase in proliferation and migration in 1% O 2 . The canonical Wnt pathway was recently shown to be activated in stem cells in low O 2 via HIF-1␣. Inhibition of Wnt signaling by DKK-1 also prevented the increase in proliferation, migration, and MMP-9 expression. Thus, MMP-9 is a key molecular effector, downstream of HIF-1␣ and Wnt activation, responsible for increased rates of NSC proliferation and migration in 1% O 2 .A frequently overlooked variable for the in vitro expansion of stem/progenitor cells is the level of O 2 in cell culture (1-3). In fact, the level of O 2 (20.9% O 2 ) used for in vitro culture is hyperoxic for cells in vivo. The lung alveoli and bloodstream typically hold ϳ14% (4, 5) and 11.5% (6 -8) O 2 , respectively, and O 2 levels in various areas of the brain range from 0.1 to 9% (5, 7, 9 -12). Recent studies have shown that the use of lower O 2 levels in culture results in increased rates of proliferation of neural stem/progenitor cells (NSCs) 2 from various embryonic or adult brain regions (12-23), virally immortalized human NSCs (23), and embryonic stem (ES) cells (3,24,25) and that these O 2 levels can also influence the differentiation of NSCs (9 -16).A large body of work has described hypoxia-inducible transcription factors as key components of the O 2 -sensing machinery that responds to lowered O 2 in cells and organisms (5,10,26,27). It has been shown that levels of HIF-1␣ protein can vary significantly over physiological ranges of O 2 (28). Although HIF-1␣ is constitutively expressed, when O 2 levels are high, the protein is hydroxylated by a family of prolyl hydroxylase enzymes, catalyzing a modification that targets HIF-1␣ for proteasomal degradation. At lower O 2 levels, the HIF-1␣ protein undergoes less hydroxylation, is stabilized, and can then translocate to the nucleus where it activates several genes that modulate the cellular response to decreas...

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Inhibition of matrix metalloproteinase-9 attenuated neural progenitor cell migration after photothrombotic ischemia

Cited by 38 publications

References 39 publications

Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal

Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

Matrix Metalloproteinase (MMP)-9 Induced by Wnt Signaling Increases the Proliferation and Migration of Embryonic Neural Stem Cells at Low O2 Levels

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