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Olfactory Ensheathing Glia: Their Application to Spinal Cord

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Olfactory Ensheathing Glia: Their Application to Spinal Cord Olfactory Ensheathing Glia: Their Application to Spinal Cord Regeneration and Remyelination Strategies Downloaded from http://meridian.allenpress.com/tscir/article-pdf/6/2/65/1985063/5wwp-t27d-lbuu-x24d.pdf by guest on 30 September 2021 Naomi Kleitman and Mary Bartlett Bunge Grafts of peripheral nerves or peripheral nervous system (PNS) Schwann cells were among the first successful strategies applied to promote regeneration in the central nervous system (CNS). However, glial cells of the PNS and CNS (Schwann cells and astrocytes, respectively) establish borders where they meet, preventing functional reconnection between regenerating axons and CNS targets. Olfactory ensheathing glia (OEG) are cells that share characteristics with both Schwann cells and astrocytes and support the growth of olfactory nerve axons into the CNS throughout life. Application of these cells to promote regeneration and remyelination in the spinal cord is reviewed. Key words: astrocyte, autotransplantation, demyelination, dorsal root entry zone, myelin, olfactory ensheathing glia, regeneration, Schwann cells, spinal cord injury, transplantation njury to the spinal cord causes the loss of cellular environment near the site of injury. neuronal cells at the level of injury, We will emphasize recent research applica- I disruption of descending and ascend- tions of a support cell population, olfactory ing axonal tracts, and, in some cases, demy- ensheathing glia (OEG), unique to the first elination of surviving tracts that renders cranial nerve. them nonfunctional. Of these, the disruption The receptor cells of the olfactory epithe- of the long descending and ascending tracts lium, whose axons make up the olfactory accounts for the majority of functional loss nerve, undergo continual cell death and re- after spinal cord injury (SCI). Descending newal throughout life. Their regenerative (supraspinal) tracts carry information from capacity is remarkable in that these processes the brain to spinal cord motor or relay neu- involve axonal growth into and new synapse rons, and ascending tracts transmit sensory formation within the adult CNS. It is thought information to the brain. Restoration of nerve that this regenerative success depends in part impulse transmission past the site of injury to on the specific properties of the OEG, cells target neurons beyond is the goal of regen- eration strategies for functional repair of SCI. Long considered unattainable, re- Naomi Kleitman, PhD, is Adjunct Associate Profes- growth of damaged spinal axons in the adult sor, The Miami Project to Cure Paralysis, Department CNS is now known to be possible. Cell of Neurological Surgery, University of Miami School of Medicine, Florida. transplantation strategies have yielded many promising results in animal models of SCI, Mary Bartlett Bunge, PhD, is Professor, The Miami although inhibition of growth within spinal Project to Cure Paralysis, Department of Cell Biology and Anatomy and Department of Neurological Sur- cord tissue beyond the grafts still poses a gery, The Chambers Family Electron Microscopy significant barrier to functional regenera- Laboratory, University of Miami School of Medicine, tion. This article will review current informa- Florida. tion on how intrinsic barriers to regeneration Top Spinal Cord Inj Rehabil 2000;6(2):65–81 in the CNS can be overcome by altering the © 2000 Thomas Land Publishers, Inc. 65 66 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 2000 which share phenotypic characteristics with ning with Ramon y Cajal and his co-workers both central glia (astrocytes) and peripheral in the early 1900s. With the advent of meth- nerve Schwann cells, but differ from both in ods to procure and purify populations of Downloaded from http://meridian.allenpress.com/tscir/article-pdf/6/2/65/1985063/5wwp-t27d-lbuu-x24d.pdf by guest on 30 September 2021 ways that have a profound influence on re- Schwann cells in culture, their use to promote generation into the CNS. CNS regeneration was proposed by Richard Bunge in 1975.2 Aguayo and co-workers3 Cellular Therapies for Spinal Cord showed that peripheral nerve bridges support Regeneration—Strengths and regeneration of injured axons from nerve Weaknesses cells situated near implants into spinal cord or optic nerve. Schwann cells appear to be the Although sprouting of injured axons oc- active component of these grafts, likely due curs during the first several weeks after in- to their production of numerous growth-pro- jury, minimal successful regeneration occurs moting surface proteins, extracellular matrix in untreated spinal cord. This is due to the (ECM) molecules including the powerful lack of adequate trophic support (i.e., nutri- growth promoter, laminin, and numerous ents that stimulate nerve growth), the pres- neurotrophic factors. Populations of ence of inhibitory molecules in the CNS, and/ Schwann cells stimulate axonal growth from or other disruptive immunological or sec- cut spinal cord axons and in cavities within ondary injury processes at the site of lesion. spinal tissue.4 Addition of exogenous neu- Attempting to make the cellular environment rotrophic factors to Schwann cell grafts near such injuries conducive to regeneration, stimulates regeneration also from supraspi- researchers have selected cellular implants nal pathways. that reproduce environments where growth It has been disappointing that axonal re- occurs normally, such as embryonic spinal entry into CNS tissue from Schwann cell cord, peripheral nerve, or Schwann cells, the grafts and embryonic spinal tissue trans- support cells of the peripheral nervous system plants has been minimal or unsuccessful. (PNS). Many excellent reviews have de- Probable reasons for this failure include the scribed these strategies, as summarized previ- presence of naturally occurring growth in- ously.1 Embryonic spinal cord transplants sur- hibitors in CNS tissue, such as those associ- vive grafting and integrate well into host cord. ated with myelin. Also problematic is the Ingrowth and egress is very limited and, in development of scar tissue in reaction to the mature hosts, these grafts do not serve as injury and/or to the grafted cells them- bridges across gaps in spinal tissue as regen- selves. This scar is thought to contain eration of long axon tracts requires. Addition proteoglycans, which arrest axonal growth. of trophic factors to embryonic spinal trans- Proteoglycans also constitute regional bor- plants improves axonal elongation into the ders during development, help sculpt ax- grafts and may improve the usefulness of the onal trajectories,5–7 and are thought to pre- grafts as relays for ascending and descending vent entry of Schwann cells into the CNS at signal transmission. spinal nerve roots.5 After traumatic injury, Peripheral nerve grafts that contain however, these natural borders become bar- growth-promoting Schwann cells have a riers to recovery. These issues have led to the long history in regeneration research, begin- exploration of cell types, OEG in particular, Olfactory Ensheathing Glia 67 Downloaded from http://meridian.allenpress.com/tscir/article-pdf/6/2/65/1985063/5wwp-t27d-lbuu-x24d.pdf by guest on 30 September 2021 Fig 1. Schematic diagram indicating the location of olfactory receptor neurons in the nasal epithelium (nasal cavity), whose axons are bundled by olfactory ensheathing glia (OEG) as they cross through the cribriform plate into the cranium. The nerve rootlets containing these bundles join to form the olfactory nerve layer, and their individual basal laminae become continuous with the glia limitans formed by astrocytes and OEG at the margin of the olfactory bulb. Axons cross the nerve layer, enter the glomerular zone, and synapse with dendrites of mitral, tufted, and periglomerular cells without directly contacting astrocytes. On the right is a tracing enlarged to illustrate the segregation of axon bundles by an ensheathing cell. that might navigate the barrier regions and (Fig. 1). Within the epithelium, olfactory chaperone growing axons through hostile receptor neurons undergo constant turnover; CNS territory. their functional mature lifetime is approxi- mately 25 days in the rodent.10 Generated Properties of OEG and Relationships to from a basal cell population, the newly grow- Other Glial Cell Types ing receptor axons extend within olfactory nerve, amidst axon fascicles ensheathed by Olfactory receptor neurons are situated in OEG. Unlike Schwann cells, OEG do not the olfactory epithelium within the nasal cav- enfold nonmyelinated axons individually in ity and the vomeronasal organ. These sen- furrows of cytoplasm. Rather, thin OEG sory neurons extend axons though the olfac- sheets surround and separate olfactory nerve tory and vomeronasal nerves to the olfactory axons into large bundles of densely packed bulb, where they synapse with dendrites of fibers8,9 (Figs. 1 and 2). When axons in the mitral, tufted, and periglomerular cells8,9 nerve reach the surface of the olfactory bulb, 68 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 2000 Downloaded from http://meridian.allenpress.com/tscir/article-pdf/6/2/65/1985063/5wwp-t27d-lbuu-x24d.pdf by guest on 30 September 2021 Fig 2. (Top) Electron micrograph of an ensheathing glial cell in the primate olfactory nerve layer. Its cytoplasmic processes (black in inset) partition bundles of 10–50 small diameter axons. (Micrograph generously contributed by James Guest, MD, PhD.) (Bottom) Electron micrograph of adult rat corticospinal axons, 3 months after grafting of a suspension
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