Astrocytic Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Promotes Oligodendrocyte Differentiation and Enhances CNS Myelination

Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2011; 31(16):6247-54. DOI: 10.1523/JNEUROSCI.5474-10.2011
Source: PubMed

ABSTRACT Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an extracellular protein and endogenous regulator of matrix metalloproteinases (MMPs) secreted by astrocytes in response to CNS myelin injury. We have previously reported that adult TIMP-1 knock-out (KO) mice exhibit poor myelin repair following demyelinating injury. This observation led us to hypothesize a role for TIMP-1 in oligodendrogenesis and CNS myelination. Herein, we demonstrate that compact myelin formation is significantly delayed in TIMP-1 KO mice, a situation that coincided with dramatically reduced numbers of white matter astrocytes in the developing CNS. Analysis of differentiation in CNS progenitor cells (neurosphere) cultures from TIMP-1 KO mice revealed a specific deficit of NG2(+) oligodendrocyte progenitor cells. Application of recombinant murine TIMP-1 (rmTIMP-1) to TIMP-1 KO neurosphere cultures evoked a dose-dependent increase in NG2(+) cell numbers, while treatment with GM6001, a potent broad-spectrum MMP inhibitor did not. Similarly, administration of rmTIMP-1 to A2B5(+) immunopanned oligodendrocyte progenitors significantly increased the number of differentiated O1(+) oligodendrocytes, while antisera to TIMP-1 reduced oligodendrocyte numbers. We also determined that A2B5(+) oligodendrocyte progenitors grown in conditioned media derived from TIMP-1 KO primary glial cultures resulted in reduced differentiation of mature O1(+) oligodendrocytes. Finally, we report that addition of rmTIMP-1 to primary glial cultures resulted in a dose-dependent proliferative response of astrocytes. Together, these findings describe a previously uncharacterized role for TIMP-1 in the regulation of oligodendrocytes and astrocytes during development and provide a novel function for TIMP-1 on myelination in the developing CNS.

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Available from: Robert H Miller, Sep 29, 2015
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    • "During EAE, constitutive TIMP-1 exerts a protective role by maintaining BBB integrity through MMP inhibition and limiting leukocyte infiltration into the CNS parenchyma (Althoff et al., 2010). During chronic EAE, TIMP-1 plays an MMP-independent role (Crocker et al., 2006), potentially by promoting oligodendrocyte progenitor differentiation and remyelination (Moore et al., 2011). While our data support an MMP independent function of TIMP-1 in promoting leukocyte migration across the glia limitans, the mechanism remains unclear. "
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    ABSTRACT: Infection of the central nervous system (CNS) with a sublethal neurotropic coronavirus (JHMV) induces a vigorous inflammatory response. CD4+ and CD8+ T cells are essential to control infectious virus but at the cost of tissue damage. An enigma in understanding the contribution of T cell subsets in pathogenesis resides in their distinct migration pattern across the blood brain barrier (BBB). CD4+ T cells transiently accumulate within the perivascular space, whereas CD8+ T cells migrate directly into the CNS parenchyma. As matrix metalloproteinases (MMPs) facilitate migration across the glia limitans, specific expression of the tissue inhibitor of MMPs (TIMP)-1 by CD4+ T cells present in the perivascular cuffs suggested that TIMP-1 is responsible for stalling CD4+ T cell migration into the CNS parenchyma. Using TIMP-1 deficient mice, the present data demonstrate an increase rather than a decrease in CD4+ T cell accumulation within the perivascular space during JHMV infection. Whereas virus control was not affected by perivascular retention of CD4+ T cells, disease severity was decreased and associated with reduced interferon-γ (IFN-γ) production. Moreover, decreased CD4+ T cell recruitment into the CNS parenchyma of TIMP-1 deficient mice was not associated with impaired T cell recruiting chemokines or MMP expression, and no compensation by other TIMP molecules was identified. These data suggest an MMP-independent role of TIMP-1 in regulating CD4+ T cell access into the CNS parenchyma during acute JHMV encephalitis.
    ASN Neuro 10/2013; 5(5). DOI:10.1042/AN20130033 · 4.02 Impact Factor
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    • "It is worth noting that PDGF can work together with bFGF to promote OPC proliferation and survival, and such ability is inversely linked to their strong inhibition for OL differentiation (Tang et al. 2000). Interestingly, TIMP-1, which was also detected at higher levels in ACDM, has recently been shown to regulate the number of NG2+ OPCs in the developing mice brain (Moore et al. 2011). One exception is CNTF. "
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    ABSTRACT: Oligodendrocyte (OL) development relies on many extracellular cues, most of which are secreted cytokines from neighboring neural cells. Although it is generally accepted that both astrocytes and microglia are beneficial for OL development, there is a lack of understanding regarding whether astrocytes and microglia play similar or distinct roles. The current study examined the effects of astrocytes and microglia on OL developmental phenotypes including cell survival, proliferation, differentiation, and myelination in vitro. Our data reveal that, although both astrocytes- and microglia-conditioned medium (ACDM and MCDM, respectively) protect OL progenitor cells (OPCs) against growth factor withdrawal-induced apoptosis, ACDM is significantly more effective than MCDM in supporting long-term OL survival. In contrast, MCDM preferentially promotes OL differentiation and myelination. These differential effects of ACDM and MCDM on OL development are highlighted by distinct pattern of cytokine/growth factors in the conditioned medium, which correlates with differentially activated intracellular signaling pathways in OPCs upon exposure to the conditioned medium.
    Brain and Behavior 09/2013; 3(5):503-14. DOI:10.1002/brb3.152 · 2.24 Impact Factor
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    • "Until recently, the contribution of astrocytes to demyelinating diseases was underestimated. However, our laboratory and others have now established a prominent role of astrocytes in vivo in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) [6-8] and axonal degeneration [9] and in vitro an increasing number of astroglial-derived factors have been identified that modulate myelination processes [7,10,11]. "
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    ABSTRACT: Astrocytes are taking the center stage in neurotrauma and neurological diseases as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting NF-kappaB activation in astrocytes, using a transgenic mouse model (GFAP-IkappaBalpha-dn mice), results in improved functional recovery, increased white matter preservation and axonal sparing following spinal cord injury (SCI). In the present study, we sought to determine whether this improvement, due to inhibiting NF-kappaB activation in astrocytes, could be the result of enhanced oligodendrogenesis in our transgenic mice. To assess oligodendrogenesis in GFAP-IkappaBalpha-dn compared to wild-type (WT) littermate mice following SCI, we used bromodeoxyuridine labeling along with cell-specific immuno-histochemistry, confocal microscopy and quantitative cell counts. To further gain insight into the underlying molecular mechanisms leading to increased white matter, we performed a microarray analysis in naive and 3 days, 3 and 6 weeks following SCI in GFAP-IkappaBalpha-dn and WT littermate mice. Inhibition of astroglial NF-kappaB in GFAP-IkappaBalpha-dn mice resulted in enhanced oligodendrogenesis 6 weeks following SCI and was associated with increased levels of myelin proteolipid protein compared to spinal cord injured WT mice. The microarray data showed a large number of differentially expressed genes involved in inflammatory and immune response between WT and transgenic mice. We did not find any difference in the number of microglia/leukocytes infiltrating the spinal cord but did find differences in their level of expression of toll-like receptor 4. We also found increased expression of the chemokine receptor CXCR4 on oligodendrocyte progenitor cells and mature oligodendrocytes in the transgenic mice. Finally TNF receptor 2 levels were significantly higher in the transgenic mice compared to WT following injury. These studies suggest that one of the beneficial roles of blocking NF-kappaB in astrocytes is to promote oligodendrogenesis through alteration of the inflammatory environment.
    Journal of Neuroinflammation 07/2013; 10(1):92. DOI:10.1186/1742-2094-10-92 · 5.41 Impact Factor
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