Spinal Cord Regeneration

Abstract

Three theories of regeneration dominate neuroscience today, all purporting to explain why the adult central nervous system (CNS) cannot regenerate. One theory proposes that Nogo, a molecule expressed by myelin, prevents axonal growth. The second theory emphasizes the role of glial scars. The third theory proposes that chondroitin sulfate proteoglycans (CSPGs) prevent axon growth. Blockade of Nogo, CSPG, and their receptors indeed can stop axon growth in vitro and improve functional recovery in animal spinal cord injury (SCI) models. These therapies also increase sprouting of surviving axons and plasticity. However, many investigators have reported regenerating spinal tracts without eliminating Nogo, glial scar, or CSPG. For example, many motor and sensory axons grow spontaneously in contused spinal cords, crossing gliotic tissue and white matter surrounding the injury site. Sensory axons grow long distances in injured dorsal columns after peripheral nerve lesions. Cell transplants and treatments that increase cAMP and neurotrophins stimulate motor and sensory axons to cross glial scars and to grow long distances in white matter. Genetic studies deleting all members of the Nogo family and even the Nogo receptor do not always improve regeneration in mice. A recent study reported that suppressing the phosphatase and tensin homolog (PTEN) gene promotes prolific corticospinal tract regeneration. These findings cannot be explained by the current theories proposing that Nogo and glial scars prevent regeneration. Spinal axons clearly can and will grow through glial scars and Nogo-expressing tissue under some circumstances. The observation that deleting PTEN allows corticospinal tract regeneration indicates that the PTEN/AKT/mTOR pathway regulates axonal growth. Finally, many other factors stimulate spinal axonal growth, including conditioning lesions, cAMP, glycogen synthetase kinase inhibition, and neurotrophins. To explain these disparate regenerative phenomena, I propose that the spinal cord has evolved regenerative mechanisms that are normally suppressed by multiple extrinsic and intrinsic factors but can be activated by injury, mediated by the PTEN/ AKT/mTOR, cAMP, and GSK3b pathways, to stimulate neural growth and proliferation.

New Aspects of Graft-induced Central Plasticity and Neuroregeneration at T 10 in a Rat Model†

“…Young has emphasized the positive effects on neuro-recovery regarding cell transplants by specific medical treatment for neuromodulation, which increases CAMP and neurotrophins, stimulating motor and sensory axons to cross glial scars and to grow long distances in white matter [3]. Spinal cord plasticity can evolve regenerative mechanisms that are normally suppressed by multiple extrinsic and intrinsic factors but can be activated by injury to stimulate neural growth and proliferation [20,21].…”

“…Until now, traumatic paraplegia by severance of the spinal cord (SC) remains an irreversible condition. Basically, current clinical treatment strategies are targeted to promote axon regeneration and outgrowth beyond the scar formation following SC avulsion [1][2][3][4][5][8][9][10][11][12][13][14][15][16][17][18][20][21][24][25][26][27][28][29][30][31][72][73][74][75][76][77][78][79][80][81][82][83][84][85] Previous experimental and clinical studies together with GB have aroused some hope that paraplegic patients might achieve some selective voluntary muscle reinnervation after grafting the first motor neuron to skeletal hip muscles [10,11,25,72,73].…”

“…Theoretically, these new axons can regenerate SNGs only by accessing their tip, whereas the remaining SNGs are covered by epineurium that is impenetrable for neuronal buds. Newly formed myelinated axons were observed in various areas of the SC, including Rexed laminae (Rxl) [1][2][3][4][5][6][7][8][9][10]. The Rexed laminae comprise a system of ten layers of gray matter (I-X), which is identified by Bror Rexed to label portions of the gray columns of the spinal cord (Figures 8 and 9), the lateral funiculus (lf), the lateral spinal nucleus (LSp), the rubrospinal (rs) tract, the medullary (caudal) reticulospinal (mrs) tract, the dorsal corticospinal (dcs) tract, the gracile fascicle (gr), the lumbar dorsal common (LDCom), and the postsynaptic dorsal column (psdc).…”

“…To date, traumatic paraplegia by severance of the spinal cord (SC) remains an irreversible functional clinical condition [1][2][3][4][5][6][7][8].…”

Comparison among bone marrow mesenchymal stem and mononuclear cells to promote functional recovery after spinal cord injury in rabbits

“…Moreover, it represents a high financial burden for the families and for the health care systems of countries 1,2 . For these reasons, scientific community has made a large effort to discover new and effective approaches to treat these conditions, aiming to promote increased nervous tissue protection, regeneration and neurologic recovery 3,4 . One of the most incident and prevalent forms of CNS lesion is the spinal cord injury (SCI), which causes motor, sensory and autonomic dysfunction 1,5 .…”