Abderrahman El Maarouf

Memorial Sloan-Kettering Cancer Center, New York City, New York, United States

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Publications (11)51.2 Total impact

  • Abderrahman El Maarouf, Damali Moyo-Lee Yaw, Urs Rutishauser
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    ABSTRACT: Motoneurons derived from mouse embryonic stemcells (mESC) begin to express low levels of polysialic acid (PSA) at the time when they acquire an ability to migrate and extend neurites. PSA is known to promote cell migration and process outgrowth/guidance in the developing nervous system. To test if experimentally-enhanced expression of PSA would augment these cellular events, the PSA-synthesizing polysialyltransferase, PST, was introduced into mESCs. In culture, the resulting higher PSA expression specifically increased neurite outgrowth and cell migration from differentiated embroid bodies. In addition, the motoneuron population obtained after sorting for HB9::GFP expression showed enhanced survival as well as extensive neurite outgrowth. Following transplantation of mESC-derived motoneurons into an adult sciatic nerve devoid of endogenous axons, the PSA augmentation increased the numbers of axons growing toward the denervated muscles. Migration of some transplanted cells inside the nerve toward muscle was also enhanced. Moreover, higher PSA expression selectively affected target innervation. It produced greater numbers of neuromuscular junctions in a predominantly fast twitch muscle and had no effect in a slow twitch muscle. These findings suggest that engineering of PSA expression in ESC could serve as an enhancement for motoneuron cell therapy.
    Cell Transplantation 03/2014; · 4.42 Impact Factor
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    ABSTRACT: There has been considerable progress in obtaining engraftable embryonic stem (ES) cell-derived midbrain dopamine neurons for cell replacement therapy in models of Parkinson's disease; however, limited integration and striatal reinnervation of ES-derived grafts remain a major challenge for future clinical translation. In this paper, we show that enhanced expression of polysialic acid results in improved graft efficiency in correcting behavioral deficits in Parkinsonian mice. This result is accompanied by two potentially relevant cellular changes: greater survival of transplanted ES-derived dopamine neurons and robust sprouting of tyrosine hydroxylase-positive processes into host tissue. Because the procedures used to enhance polysialic acid are easily translated to other cell types and species, this approach may represent a general strategy to improve graft integration in cell-based therapies.
    STEM CELLS TRANSLATIONAL MEDICINE 12/2013; · 3.60 Impact Factor
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    ABSTRACT: In vertebrates, polysialic acid (PSA) is typically added to the neural cell adhesion molecule (NCAM) in the Golgi by PST or STX polysialyltransferase. PSA promotes plasticity, and its enhanced expression by viral delivery of the PST or STX gene has been shown to promote cellular processes that are useful for repair of the injured adult nervous system. Here we demonstrate a new strategy for PSA induction on cells involving addition of a purified polysialyltransferase from Neisseria meningitidis (PST(Nm)) to the extracellular environment. In the presence of its donor substrate (CMP-Neu5Ac), PST(Nm) synthesized PSA directly on surfaces of various cell types in culture, including Chinese hamster ovary cells, chicken DF1 fibroblasts, primary rat Schwann cells, and mouse embryonic stem cells. Similarly, injection of PST(Nm) and donor in vivo was able to produce PSA in different adult brain regions, including the cerebral cortex, striatum, and spinal cord. PSA synthesis by PST(Nm) requires the presence of the donor CMP-Neu5Ac, and the product could be degraded by the PSA-specific endoneuraminidase-N. Although PST(Nm) was able to add PSA to NCAM, most of its product was attached to other cell surface proteins. Nevertheless, the PST(Nm)-induced PSA displayed the ability to attenuate cell adhesion, promote neurite outgrowth, and enhance cell migration as has been reported for endogenous PSA-NCAM. Polysialylation by PST(Nm) occurred in vivo in less than 2.5 h, persisted in tissues, and then decreased within a few weeks. Together these characteristics suggest that a PST(Nm)-based approach may provide a valuable alternative to PST gene therapy.
    Journal of Biological Chemistry 07/2012; 287(39):32770-9. · 4.65 Impact Factor
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    ABSTRACT: Schwann cell (SC) implantation after spinal cord injury (SCI) promotes axonal regeneration, remyelination repair, and functional recovery. Reparative efficacy, however, may be limited because of the inability of SCs to migrate outward from the lesion-implant site. Altering SC cell surface properties by overexpressing polysialic acid (PSA) has been shown to promote SC migration. In this study, a SCI contusion model was used to evaluate the migration, supraspinal axon growth support, and functional recovery associated with polysialyltransferase (PST)-overexpressing SCs [PST-green fluorescent protein (GFP) SCs] or controls (GFP SCs). Compared with GFP SCs, which remained confined to the injection site at the injury center, PST-GFP SCs migrated across the lesion:host cord interface for distances of up to 4.4 mm within adjacent host tissue. In addition, with PST-GFP SCs, there was extensive serotonergic and corticospinal axon in-growth within the implants that was limited in the GFP SC controls. The enhanced migration of PST-GFP SCs was accompanied by significant growth of these axons caudal to lesion. Animals receiving PST-GFP SCs exhibited improved functional outcome, both in the open-field and on the gridwalk test, beyond the modest improvements provided by GFP SC controls. This study for the first time demonstrates that a lack of migration by SCs may hinder their reparative benefits and that cell surface overexpression of PSA enhances the ability of implanted SCs to associate with and support the growth of corticospinal axons. These results provide further promise that PSA-modified SCs will be a potent reparative approach for SCI. © 2012 Wiley Periodicals, Inc.
    Glia 05/2012; 60(6):979-92. · 5.07 Impact Factor
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    ABSTRACT: Spinal lamina II, where nociceptive C-fibers terminate, expresses high amounts of the polysialylated form of neural cell adhesion molecule (PSA-NCAM). While enzymatic removal of the PSA moiety from NCAM did not affect normal sensitivity to thermal stimuli, it exacerbated nerve injury-induced neuropathic hyperalgesia. The genetic removal of the NCAM core protein also did not alter thermal sensitivity. However in the presence of a peripheral nerve injury, NCAM-null mutants exhibited a complete suppression of thermal hyperalgesia. This strong NCAM mutant phenotype appears to involve the long form of NCAM's cytoplasmic domain, in that it is duplicated by selective genetic deletion of the NCAM-180 isoform. PSA appears therefore to provide a mechanism for modulation of chronic sensory overload, by means of attenuation of the activity of the NCAM-180 isoform, which reduces nociceptive transmission.
    Experimental Neurology 12/2011; 233(2):866-70. · 4.65 Impact Factor
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    ABSTRACT: Neurons that express high levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in adult spinal substantia gelatinosa also express the μ-opioid receptor. While PSA removal from NCAM by spinal intrathecal injection of endoneuraminidase-N (endo-N) did not detectably change opioid receptor expression, morphine-induced analgesia was significantly increased. This analgesic strengthening was detected as early as 15 min after endo-N treatment and persisted for at least 7 days. In addition, the tolerance that develops with chronic morphine treatment was overcome in the absence of PSA. Interestingly, the same effects on analgesia and tolerance were also produced by selective deletion of the NCAM-180 isoform.
    Brain research 06/2011; 1404:55-62. · 2.46 Impact Factor
  • Athanasios K Petridis, Abderrahman El Maarouf
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    ABSTRACT: New progenitor cells in the subventricular zone (SVZ) migrate rostrally and differentiate into interneurons in the olfactory bulb (OB) throughout life. Brain-derived neurotrophic factor (BDNF) may influence the normal progression of this migration. In the present study, mouse SVZ explant cultures were used to investigate how BDNF modulates the behavior of these migrating progenitors. Concentrations of BDNF in the physiological range (e.g. 1ng/mL) stimulated migration, whereas doses of 10 ng/mL or higher induced SVZ cell differentiation and reduced migration. Pharmacological inhibition of the mitogen-activated protein kinase (MAPK) pathway blocked the BDNF-induced differentiation of SVZ progenitors, indicating that differentiation of SVZ progenitors in response to high-dose BDNF is initiated through MAPK. Physiological concentrations of BDNF, like the presence of polysialic acid in the tissue, stimulated migration of cells from the explant without affecting the speed at which this occurs. Interestingly, in vivo immunohistochemical and molecular analysis showed similar levels of BDNF in both the SVZ and OB; that is, there was no positive gradient attracting SVZ cells towards the OB. Our data show that SVZ cells respond differently to different concentrations of BDNF.
    Journal of Clinical Neuroscience 02/2011; 18(2):265-70. · 1.25 Impact Factor
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    Abderrahman El Maarouf, Urs Rutishauser
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    ABSTRACT: Polysialic acid (PSA) is a highly hydrated polymer whose presence at the cell surface can reduce cell interactions, and thereby increase tissue and cellular plasticity. Given its ability to create a permissive environment for cell migration and axonal growth, the potential of engineered over-expression of PSA to promote tissue repair has been explored in the adult CNS. Several promising results have been obtained that suggest that PSA engineering may become a valuable therapeutic tool.
    Advances in experimental medicine and biology 01/2010; 663:137-47. · 1.83 Impact Factor
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    Abderrahman El Maarouf, Athanasios K Petridis, Urs Rutishauser
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    ABSTRACT: Polysialic acid (PSA), a large cell-surface carbohydrate that regulates cell interactions, is used during vertebrate development to promote precursor cell migration and axon path-finding. The induction of PSA expression in damaged adult CNS tissues could help them to rebuild by creating conditions permissive for architectural remodeling. This possibility has been explored in two contexts, the regeneration of axons and the recruitment of endogenous neural precursors to a lesion. Glial scars that form at CNS injury sites block axon regeneration. It has been found that transfection of scar astrocytes by a viral vector encoding polysialyltransferase leads to sustained expression of high levels of PSA. With this treatment, a substantial portion of severed corticospinal tract axon processes were able to grow through a spinal injury site. In the studies of precursor cell migration to a cortical lesion, it was found that induced PSA expression in a path extending from the subventricular zone to a lesion near the cortical surface increased recruitment of BrdU/nestin-positive cells along the path and into the injury site. These displaced precursors were able to differentiate in a regionally appropriate manner. These findings suggest that induced PSA expression can be used as a strategy for promoting tissue repair involving both replacement of cells and rebuilding of neural connections.
    Proceedings of the National Academy of Sciences 12/2006; 103(45):16989-94. · 9.81 Impact Factor
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    ABSTRACT: Under chronic conditions of neuropathic pain, nociceptive C terminals are lost from their target region in spinal lamina II, leading to reduced thermal hyperalgesia. This region of the spinal cord expresses high levels of polysialic acid (PSA), a cell surface carbohydrate known to weaken cell-cell interactions and promote plasticity. Experimental removal of PSA from the spinal cord exacerbates hyperalgesia and results in retention of C terminals, whereas it has no effect on plasticity of touch Abeta fibers and allodynia. We propose that expression of PSA at this stress pathway relay point could serve to protect central circuitry from chronic sensory overload.
    Proceedings of the National Academy of Sciences 09/2005; 102(32):11516-20. · 9.81 Impact Factor
  • Abderrahman El Maarouf, Urs Rutishauser
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    ABSTRACT: Developing chick retinotectal projections extend rostrally in the superficial stratum opticum of the tectum until they reach their appropriate target zone. They then penetrate, arborize, and form synapses within distinct tectal retinorecipient layers. In this study, we show that the polysialylated neural cell adhesion molecule is expressed both on the membrane of these developing projections and in the stratum opticum and retinorecipient layers during the period of optic innervation. On this basis, the role of polysialic acid was analyzed with respect to both trajectory and arborization in the tectum, using confocal imaging of DiI-labeled retinotectal fibers in whole-mount tecta of embryos pretreated with a polysialic acid-specific degrading enzyme, endoneuraminidase N. The removal of polysialic acid caused several distinct abnormalities, including random dorsal/ventral meandering of fibers in the stratum opticum, a distorted branching and extension of arbors in the retinorecipient layers, and inappropriate synaptic vesicle accumulation in pretarget areas. These findings indicate that the unique ability of polysialic acid to regulate different types of cell interactions is an essential component of axon behavior during multiple steps of tectal target innervation.
    The Journal of Comparative Neurology 06/2003; 460(2):203-11. · 3.66 Impact Factor