Cytokine-mediated modulation of MMPs and TIMPs in multipotential neural precursor cells
Introduction
Regeneration of myelin sheaths in demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis (MS) requires either the mobilization of endogenous precursor cells or transplantation of neural precursor cells (NPCs), as a source of myelin-forming cells (Duncan et al., 1997, Cao et al., 2002, Ben-Hur et al., 2005). The participation of endogenous precursors or of transplanted NPCs in the remyelinating processes is dependent on their ability to migrate into diseased tissue and regenerate functional myelin sheaths. In experimental allergic encephalomyelitis (EAE), an animal model of brain inflammation and MS, there is reactive migration of endogenous subventricular PSA-NCAM+ precursor cells to the white matter (Picard-Riera et al., 2002). Similarly, the inflammatory process during EAE triggers the migration and differentiation of transplanted NPCs into the inflamed white matter (Ben-Hur et al., 2003b). The specific biological mechanisms by which the inflammatory process mobilizes NPCs have not yet been elucidated. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which play a central role in MS pathology, were found to inhibit NPCs proliferation and to enhance the outward migration of the cells from spheres in vitro (Ben-Hur et al., 2003a). Recently, it was also shown that the chemokine SDF-1, acting via the chemokine receptor CXCR4, mediates transplanted neural stem cell migration towards the ischemic penumbra of experimental stroke (Imitola et al., 2004). In addition, hepatocyte growth factor induces the migration of oligodendrocyte progenitor cells in vitro (Lalive et al., 2005).
In both physiological and pathological conditions, the process of migration (or cells' motility and penetration) through the surrounding tissue necessitates the breakdown of the extracellular matrix (ECM). This process is mediated by degrading proteases, among them the matrix metalloproteinases (MMPs) family of enzymes. The members of the MMP family, which to date include over 23 human gene products, are classified into subgroups according to their basic structure and substrate specificity (Nagase and Woessner, 1999). The gelatinases, MMP-2 and -9, capable of degrading ECM components such as collagen type IV, laminin and fibronectin, are key enzymes in the processes of immune cell migration as well as wound healing (or repair/remyelination) as observed during neuroinflammatory disorders (Miller et al., 2002). MMPs are tightly regulated by molecules controlling their activation and by endogenous tissue inhibitors of MMPs (TIMPs) (Visse and Nagase, 2003). Four distinct TIMPs have been identified to date (Gomez et al., 1997). While most TIMPs react with all activated MMPs, TIMP-2 bind to pro-MMP-2 and TIMP-1 inhibits specifically pro-MMP-9 (Fassina et al., 2000). Regulation of MMPs at the transcription level involves cytokines, chemokines and growth factors (Borden and Heller, 1997, Yong et al., 2001).
In spite of the accumulating evidence on MMPs/TIMPs involvement in CNS injury and MS, little is known regarding their expression and regulation in NPCs, which give rise to the remyelinating cells in the CNS. The aims of the present study were to characterize the profile of MMPs and their endogenous inhibitors (TIMPs) expressed in rat NPCs, and to examine the regulatory effect(s) of inflammatory mediators on this expression and secretion profile. Specifically, we investigated how TNF-α, IFN-γ and IFN-β modulate the expression of the gelatinases MMP-2 and MMP-9, and their specific inhibitors TIMP-2 and TIMP-1. Our findings provide a mechanism by which the inflammatory process may mobilize neural precursor cells.
Section snippets
Isolation of striatal precursor cells and growth of neurospheres
Striata were dissected from newborn Lewis rats' brains. Following removal of meninges, the tissue was minced, digested in 0.025% Trypsin for 20 min and dissociated with a 5 ml pipette to a single cell suspension. Debris was removed by centrifugation through a 4% BSA layer. The cells were suspended in serum-free F12/DMEM medium (Biological Industries, Bet Haemek, Israel) supplemented with 10 mg% human apo-transferin, 1 mM sodium-pyruvate, 0.05% BSA, 10 ng/ml d-biotin, 30 nM sodium-selenite,
TNF-α and IFN-γ induce gelatinases activity in neural precursor cells
Determination of gelatinase activity by zymography indicated that NPCs secrete constitutively pro-MMP-2, pro-MMP-9 and active-MMP-2 protein. The level of the secreted active-form of MMP-9 by these cells was too low to allow its quantification in this assay (Fig. 1A). Incubation of NPCs with TNF-α (1–100 ng/ml) or INF-γ (10–1000 U/ml) led to a significant dose-dependent elevation of secreted pro-MMP-9 protein by 1.6- or 1.3-fold, respectively (Fig. 1B, p < 0.0001). In a similar manner, both
Discussion
The migration of neural precursors in the brain is an essential component of any regenerative process following injury. In view of recent observations on the mobilization of precursors by the brain inflammatory process and by inflammatory cytokines (Ben-Hur et al., 2003a, Ben-Hur et al., 2003b, Imitola et al., 2004), we examined here the effects of key inflammatory cytokines on MMP and TIMP production by neural precursor cells. Our results show that inflammatory cytokines modulate the
Acknowledgements
This work was supported by the Rappaport Institute for Research in the Medical Sciences and the Technion-Israel Institute of Technology, Haifa, Israel, and by the Lena P. Harvey Research Fund. The work is dedicated in the memory of Rachel Kol who was a driving spirit in the Neuroimmunology lab. We thank Dr. Sarah Shapiro for helpful assistance with the data assessment and discussion.
References (33)
- et al.
Gelatinases (MMP-2 and MMP-9) are preferentially expressed by Th1 vs. Th2 cells
J. Neuroimmunol.
(2005) - et al.
Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells
Mol. Cell. Neurosci.
(2003) - et al.
Methylprednisolone attenuates interferon-β induced expression of HLA-DR on monocytes
J. Neuroimmunol.
(1996) - et al.
Repair of myelin disease: strategies and progress in animal models
Mol. Med. Today
(1997) - et al.
Modulation of monocytes matrix metalloproteinase-2, MT1-MMP and TIMP-2 by interferon-γ and -β: implications to multiple sclerosis
J. Neuroimmunol.
(2002) - et al.
Immunoregulatory effects of interferon-β and interacting cytokines on human vascular endothelial cells. Implications for multiple sclerosis
J. Neuroimmunol.
(1996) - et al.
Matrix metalloproteinases
J. Biol. Chem.
(1999) - et al.
Gelatinase B: a tuner and amplifier of immune functions
Trends Immunol.
(2001) - et al.
Tumor necrosis factor-α modulates the proliferation of neural progenitors in the subventricular/ventricular zone of adult rat brain
Neurosci. Lett.
(2000) - et al.
The role of IL-18 and IL-12 in the modulation of matrix metalloproteinases and their tissue inhibitors in monocytic cells
Int. Immunol.
(2002)
IFN-gamma low production capacity in type I diabetes mellitus patients at onset of disease
Exp. Clin. Endocrinol. Diabetes
Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis
Glia
Stem cell therapy for myelin diseases
Curr. Drug Targets
Regulation of endothelial matrix metalloproteinase-2 by hypoxia/reoxygenation
Circ. Res.
Transcriptional control of matrix metalloproteinases and tissue inhibitors of metalloproteinases
Crit. Rev. Eukaryot. Gene Expr.
Stem cell repair of central nervous system injury
J. Neurosci. Res.
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