Myelination and remyelination in the regenerating visual system of the goldfish

Summary The remyelination of regenerated optic axons was investigated in goldfish following either optic nerve crush or ouabain retinal intoxication. Axons grown after nerve crushing acquire thinner myelin sheaths than axons originating from reconstituted ganglion cells. If axons of reconstituted ganglion cells are crushed and allowed to regenerate, the subsequent myelination is weaker than that of control axons not interrupted by crushing, but stronger than that of axons of preexisting retinal ganglion cells.The present results suggest that a neuron is capable of inducing a normally developed myelin sheath when its axon contacts an oligodendrocyte the first time, whereas a neuron whose axon contacts an oligodendrocyte the second time is not capable of forming a normal myelin sheath in the adult animal. The present results also support the notion that the oligodendrocyte requires a neuronal signal for myelin sheath formation.Supported by the Deutsche Forschungsgemeinschaft (Wo 215/5)     

The immunoregulatory and neuroprotective effects of human adipose derived stem cells overexpressing IL-11 and IL-13 in the experimental autoimmune encephalomyelitis mice

Multiple sclerosis (MS) is an inflammatory demyelination disease in the central nervous system (CNS) characterized by incomplete endogenous remyelination in the chronic phase. A shift of the balance between pro and anti-inflammatory cytokines is one of the important markers in the pathogenesis of MS. This study aimed to evaluate the effects of human adipose derived stem cells (hADSCs) overexpressing interleukin 11 and interleukin 13 (IL-11, 13-hADSCs) on the experimental autoimmune encephalomyelitis (EAE), an animal model of MS. 12 days after immunization of C57Bl/6 female mice with MOG35-55 and initial clinical symptoms appearance, the IL-11, 13-hADSCs were injected via the tail vein into the EAE mice. Then, the mice were sacrificed at 30 days post-immunization (DPI) and the spinal cords of experimental groups were extracted for histopathological and real-time RT-PCR studies. The results indicated that the clinical scores and mononuclear cells infiltration into the spinal cords of EAE mice were significantly reduced in mice treated with IL-11, 13-hADSCs. Likewise, the remyelination and oligodendrogenesis were significantly enhanced in the mentioned treatment group. Real-time results demonstrated that pro/anti-inflammatory cytokine genes expression was reversed in IL-11, 13-hADSCs treatment group in comparison to the untreated EAE group. Expression of IL-11 as a neurotrophic cytokine and IL-13 as an anti-inflammatory cytokine by hADSCs could increase the immunomodulatory and neuroprotective effects of hADSCs and be a powerful candidate in stem cell therapy for future treatment of MS.     

Neurophysiological evidence for long-term repair of MS lesions: implications for axon protection

After recovery from the acute stage of optic neuritis, a marked prolongation in the latencies of visual evoked potentials (VEPs) is typically observed. We have conducted three studies (one cross-sectional, two prospective), aimed at elucidating the progressive shortening of VEP latency, which frequently ensues over the following months or years. This has been shown to be a progressive process and a prevalent tendency in the patient population, proceeding for more than 2 years in spite of the fact that very little functional improvement in vision occurs after the first few months. We argue that the underlying process of repair is most likely to involve remyelination of demyelinated optic nerve axons. Rather than restoration of visual function (which may be virtually complete after as short a period as 3 months), the main importance of the long-term myelin repair process may consist in protecting demyelinated axons from subsequent, permanent degeneration. In the VEPs of the acutely unaffected fellow eyes followed up over 3 years, we observed an asymptomatic deterioration, possibly due to insidious processes of demyelination and/or axonal degeneration. Even in the relapsing/remitting stage of MS, therefore, there is electrophysiological evidence for involvement of clinically asymptomatic axons, which, in the later stages, may be manifested as progressive functional deterioration.     

Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis

The behavior and myelinogenic properties of glial cells have been well documented following transplantation into regions of focal experimental demyelination in animal models. However, the ability of glial cell preparations to remyelinate in such models does not necessarily indicate that their transplantation into demyelinated lesions in clinical disease will be successful. One of the precluding factors in this regard is a greater understanding of the environmental conditions that will support transplant-mediated remyelination. In this study, we determined whether the complex and reactive CNS environment of the mouse hepatitis virus (MHV) model of multiple sclerosis (MS) could support transplant-mediated remyelination. Striatal neural precursors derived from postnatal day 1 mice were committed to a glial cell lineage and labeled. Immunohistochemical staining indicated that this population generated >93% glial cells following differentiation in vitro. Transplantation of glial-committed progenitor cells into the T8 spinal cord of MHV-infected mice demonstrating complete hindlimb paralysis resulted in migration of cells up to 12 mm from the implantation site and remyelination of up to 67% of axons. Transplanted-remyelinated animals contained approximately 2x the number of axons within sampled regions of the ventral and lateral columns as compared to non-transplanted animals, suggesting that remyelination is associated with axonal sparing. Furthermore, transplantation resulted in behavioral improvement. This study demonstrates for the first time that transplant-mediated remyelination is possible in the pathogenic environment of the MHV demyelination model and that it is associated with locomotor improvement.     

Oligodendrocyte production and myelin recovery in heterozygous jimpy mice: An autoradiographic study

Jimpy is a genetic disorder of mouse resulting in hypomyelination. In this study oligodendrocyte proliferation was examined in heterozygous carriers of the jimpy gene. The incorporation of [3H]-thymidine into DNA is increased in jimpy heterozygotes compared to controls. An autoradiographic analysis indicated that oligodendrocytes are the predominant neuroglial cell type being produced in the brain at the ages studied in both heterozygotes and control animals. In addition, the total number of labeled oligodendrocytes was increased in the heterozygote animals compared to controls. These results, taken together, indicate that the rate of oligodendrocyte production is greater in jimpy heterozygotes than in control animals. We have previously shown that young jimpy heterozygotes have a reduced myelin content and older heterozygotes do not. The increased rate of oligodendrocyte production, demonstrated in this study, is most likely responsible for the increasing myelin content in the heterozygote. Further study of the cellular interactions which trigger oligodendrocyte production and myelin recovery in the jimpy heterozygote may be relevant to remyelination in other disease states, including those affecting humans.     

Aberrant remyelination of axons after heat injury in the dorsal funiculus of rat spinal cord

Summary We studied the course of demyelination and subsequent remyelination of nerve fibers after heat injury in the dorsal funiculus of the rat spinal cord. Four weeks after heat treatment, we observed, in addition to normally remyelinated axons, a few aberrantly remyelinated axons which had both CNS-and PNS-type myelin sheaths: the CNS-type myelin sheaths were always situated inside the PNS-type sheaths. This finding indicates that in some conditions Schwann cells can form myelin sheaths around those formed by oligodendrocytes.     

The role of NCAM in remyelination

The neural cell adhesion molecule (NCAM) is expressed by myelinating precursor cells in neonatal mouse spinal cord and by remyelinating cells after chemically induced demyelination in adult mouse. It shows tempting suggestions about its possible involvement in the reparative mechanisms and the remyelination processes that take place in multiple sclerosis (MS). In fact, its levels progressively increase in the cerebrospinal fluid (CSF) of acute MS patients subjected to steroid treatment, paralleling the progressive clinical improvement after the attack. Such an increase is not found in nacute MS patients not treated with steroids nor in non-acute patients subjected to the same steroid treatment. Received: 15 June 2001 / Accepted in revised form: 24 January 2002     

Ultrastructural findings in spongy degeneration of white matter in silver foxes (Vulpes vulpes)

Summary Spongy degeneration of white matter in silver foxes is a naturally occurring, hereditary disorder. We report ultrastructural findings in the upper cervical cord of five perfusion-fixed foxes that were examined between 5 weeks and 2 1/4 years after the onset of clinical signs. Large cytoplasmic vacuoles in oligodendrocytes were present in the foxes examined 5, 12 and 20 weeks after the onset. Other early features of the disease were severe vacuolation of myelin sheaths, demyelination, expansion of extracellular spaces and hypertrophy of astrocytes. Evidence of partial demyelination as well as demyelination of entire internodes was found. In the later stages of the disease, the vacuolation was largely resolved but a marked astrogliosis persisted and numerous remyelinated axons were present in the gliotic areas. Vacuolation of oligodendrocytes and partial demyelination has not previously been seen together in a single disease process. The relationship between oligodendrocyte vacuolation, myelin sheath vacuolation and demyelination is discussed. It is concluded that the present condition is due to a primary damage to oligodendrocytes; however, the underlying biochemical lesion is not known.A part of this study was performed while G. Hagen had a period of study at the University of Cambridge (Agricultural Research Council of Norway (NLVF), grant No. 555.027)     

Cell cultures enriched in oligodendrocytes from the central nervous system of trout in terms of phenotypic expression exhibit parallels with cultured rat Schwann cells

Oligodendrocytes were isolated from the white matter of young trout by Percoll density centrifugation of enzymatically dissociated tissue and cultured on poly-D-lysine-coated petri dishes. Using antisera recognizing myelin-specific compounds of fish CNS (36K, IP2) up to 72% of the isolated cells could be identified as oligodendrocytes with an average yield of 4 x 10(6) cells per gram of wet tissue. Taken in culture, the cells rapidly regenerated their processes and soon acquired a morphology closely resembling mammalian oligodendrocytes in vitro. On the other hand, in terms of phenotypic expression, interesting parallels were revealed with the known in vitro behavior of Schwann cells: Galactocerebroside, which in mammalian oligodendrocytes is persistently expressed over longer periods of time in vitro, rapidly disappeared from the surface of cultured trout oligodendrocytes. In contrast, the fish CNS myelin glycoprotein IP2, which like IP1 is immunologically related to the major myelin product of Schwann cells, P0, was continuously expressed over several weeks in culture. Two other myelin protein constituents, 36K and IP1, transiently declined in vitro, but later on fully reappeared in the glial cells of trout. The present cell culture system offers an experimental model for studying in vitro the factors underlying oligodendroglial regeneration and remyelination in the fish CNS.