PEDF Is a Novel Oligodendrogenic Morphogen Acting on the Adult SVZ and Corpus Callosum

Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2012; 32(35):12152-64. DOI: 10.1523/JNEUROSCI.0628-12.2012
Source: PubMed


Pigment epithelium-derived factor (PEDF) is a serine protease inhibitor (serpin) protein with well established neuroprotective and anti-angiogenic properties. Recent studies have also shown that PEDF enhances renewal of adult subventricular zone (SVZ) neural precursors. In neurosphere cultures prepared from the SVZ of adult mice, we found that addition of recombinant PEDF to the medium enhanced expressions of oligodendroglial lineage markers (NG2 and PDGFrα) and transcription factors (Olig1, Olig2, and Sox10). Similarly, continuous PEDF administration into the lateral ventricles of adult glial fibrillary acidic protein:green fluorescent protein (GFAP:GFP) transgenic mice increased the proportions of GFAP:GFP+ and GFAP:GFP- SVZ neural precursors coexpressing oligodendroglial lineage markers and transcription factors. Notably, PEDF infusion also resulted in an induction of doublecortin- and Sox10 double-positive cells in the adult SVZ. Immunoreactive PEDF receptor was detectable in multiple cell types in both adult SVZ and corpus callosum. Furthermore, PEDF intracerebral infusion enhanced survival and maturation of newly born oligodendroglial progenitor cells in the normal corpus callosum, and accelerated oligodendroglial regeneration in lysolecithin-induced corpus callosum demyelinative lesions. Western blot analysis showed a robust upregulation of endogenous PEDF in the corpus callosum upon lysolecithin-induced demyelination. Our results document previously unrecognized oligodendrotrophic effects of recombinant PEDF on the adult SVZ and corpus callosum, demonstrate induction of endogenous CNS PEDF production following demyelination, and make PEDF a strong candidate for pharmacological intervention in demyelinative diseases.

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    • "In fact, PEDF infusion induces the survival and maturation of local OPCs in the corpus callosum into myelinating oligodendrocytes. In vitro, PEDF increases the commitment of glial fibrillary acidic protein (GFAP)+ stem cells toward the oligodendrocyte lineage by inducing the expression of transcription factors related to oligodendrogenesis such as Sox10, Olig1 and Olig2 (Sohn et al., 2012). Similarly, FGF-2 signaling is crucial during the onset of perinatal oligodendrogenesis in the SVZ. "
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    ABSTRACT: Neural stem cells (NSCs) from the subventricular zone (SVZ) have been indicated as a source of new oligodendrocytes to use in regenerative medicine for myelin pathologies. Indeed, NSCs are multipotent cells that can self-renew and differentiate into all neural cell types of the central nervous system. In normal conditions, SVZ cells are poorly oligodendrogenic, nevertheless their oligodendrogenic potential is boosted following demyelination. Importantly, progressive restriction into the oligodendrocyte fate is specified by extrinsic and intrinsic factors, endocannabinoids being one of these factors. Although a role for endocannabinoids in oligodendrogenesis has already been foreseen, selective agonists and antagonists of cannabinoids receptors produce severe adverse side effects. Herein, we show that hemopressin (Hp), a modulator of CB1 receptors, increased oligodendroglial differentiation in SVZ neural stem/progenitor cell cultures derived from neonatal mice. The original results presented in this work suggest that Hp and derivates may be of potential interest for the development of future strategies to treat demyelinating diseases.
    Frontiers in Cellular Neuroscience 02/2014; 8:59. DOI:10.3389/fncel.2014.00059 · 4.29 Impact Factor
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    • "CNTF LPC demyelinated rodent O Recruitment Vernerey et al., 2013 NGF EAE rat O Differentiation Aloe and Micera, 1998 IGF-1 Cell culture N Differentiation Brooker et al., 2000 PEDF Transgenic mouse O Fate commitment Sohn et al., 2012 PDGF Transgenic mouse O Proliferation Jackson et al., 2006 VEGF Unlesioned rat N Proliferation Jin et al., 2002 BDNF Unlesioned rat N Proliferation Pencea et al., 2001b MOLECULE Reelin LPC demyelinated mouse N Recruitment Courtès et al., 2011 Netrin 1 LPC demyelinated mouse O Recruitment Cayre et al., 2013 Chordin LPC demyelinated mouse O Recruitment Jablonska et al., 2010 Noggin Cuprizone demyelinated mouse O Proliferation Cate et al., 2010 Fate commitment LPC, Lysolecithin; O, Oligodendrogenesis; N, Neurogenesis; EAE, experimental autoimmune encephalomyelitis; HB-EGF, Heparin-binding epidermal growth factor; "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic neurological disability. A promising perspective for future therapy of MS is the regeneration of lesions with replacement of the damaged oligodendrocytes or neurons. Therapies targeting to the enhancement of endogenous remyelination, aim to promote the activation of either the parenchymal oligodendrocyte progenitor cells or the subventricular zone-derived neural stem cells (NSCs). Less studied but highly potent, is the strategy of neuronal regeneration with endogenous NSCs that although being linked to numerous limitations, is anticipated to ameliorate cognitive disability in MS. Focusing on the forebrain, this review highlights the role of NSCs in the regeneration of MS lesions.
    Frontiers in Neuroscience 01/2014; 8:454. DOI:10.3389/fnins.2014.00454 · 3.66 Impact Factor
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    • "The recently described proteins mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) represent modern, evolutionary conserved neurotrophin family members that protect and functionally restore dopaminergic neurons [17]. Pigment epithelium-derived factor (PEDF) is a serine protease inhibitor (serpin) protein that exhibits well-documented neuroprotective and anti-angiogenic attributes [18]. The angiogenic-specific effect and neurotrophic activity of vascular endothelial growth factor (VEGF) also makes this trophic protein an attractive target for improving regenerative processes in a damaged CNS [17]. "
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    ABSTRACT: Stem/progenitor cells (SPCs) demonstrate neuro-regenerative potential that is dependent upon their humoral activity by producing various trophic factors regulating cell migration, growth, and differentiation. Herein, we compared the expression of neurotrophins (NTs) and their receptors in specific umbilical cord blood (UCB) SPC populations, including lineage-negative, CD34(+), and CD133(+) cells, with that in unsorted, nucleated cells (NCs). The expression of NTs and their receptors was detected by QRT-PCR, western blotting, and immunofluorescent staining in UCB-derived SPC populations (i.e., NCs vs. lineage-negative, CD34(+), and CD133(+) cells). To better characterize, global gene expression profiles of SPCs were determined using genome-wide RNA microarray technology. Furthermore, the intracellular production of crucial neuro-regenerative NTs (i.e., BDNF and NT-3) was assessed in NCs and lineage-negative cells after incubation for 24, 48, and 72 h in both serum and serum-free conditions. We discovered significantly higher expression of NTs and NT receptors at both the mRNA and protein level in lineage-negative, CD34(+), and CD133(+) cells than in NCs. Global gene expression analysis revealed considerably higher expression of genes associated with the production and secretion of proteins, migration, proliferation, and differentiation in lineage-negative cells than in CD34(+) or CD133(+) cell populations. Notably, after short-term incubation under serum-free conditions, lineage-negative cells and NCs produced significantly higher amounts of BDNF and NT-3 than under steady-state conditions. Finally, conditioned medium (CM) from lineage-negative SPCs exerted a beneficial impact on neural cell survival and proliferation. Collectively, our findings demonstrate that UCB-derived SPCs highly express NTs and their relevant receptors under steady-state conditions, NT expression is greater under stress-related conditions and that CM from SPCs favorable influence neural cell proliferation and survival. Understanding the mechanisms governing the characterization and humoral activity of subsets of SPCs may yield new therapeutic strategies that might be more effective in treating neurodegenerative disorders.
    PLoS ONE 12/2013; 8(12):e83833. DOI:10.1371/journal.pone.0083833 · 3.23 Impact Factor
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