Transplantation of glial cells enhances action potential conduction of amyelinated spinal cord axons in the myelin-deficient rat.

Abstract

A central issue in transplantation research is to determine how and when transplantation of neural tissue can influence the development and function of the mammalian central nervous system. Of particular interest is whether electrophysiological function in the traumatized or diseased mammalian central nervous system can be improved by the replacement of cellular elements that are missing or damaged. Although it is known that transplantation of neural tissue can lead to functional improvement in models of neurological disease characterized by neuronal loss, less is known about results of transplantation in disorders of myelin. We report here that transplantation of glial cells into the dorsal columns of neonatal myelin-deflcient rat spinal cords leads to myelination and a 3-fold increase in conduction velocity. We also show that impulses can propagate into and out of the transplant region and that axons myelinated by transplanted cells do not have impaired frequency-response properties. These results demonstrate that myelination following central nervous system glial cell transplantation enhances action potential conduction in myelin-deficient axons, with conduction velocity approaching normal values.The ability of transplanted glial cells to ensheath axons and synthesize myelin when transplanted into dysmyelinating mutants or chemically created models of demyelination has been studied extensively (1-6). Until now the primary assay of myelin-forming grafts has of necessity been anatomical rather than functional or electrophysiological. However, the formation of myelin by transplanted cells does not in itself ensure secure impulse conduction. Impulse conduction after glial cell transplantation depends not only on myelination but on deployment of adequate numbers and types of ion channels at the newly formed nodes of Ranvier (7-9). Moreover, incomplete or patchy remyelination might be expected to lead to conduction failure due to impedance mismatch, which occurs at junctions between myelinated and nonmyelinated axon regions (10, 11); similarly, failure to form mature paranodal axoglial junctions can shunt action current and interfere with conduction (12, 13). In the present experiments, we transplanted central nervous system (CNS) myelin-forming cells into the spinal cord of the myelin-deficient (md) rat, a mutant that lacks CNS myelin, and studied conduction properties of the axons in the region of transplantation. The absence of host myelin in this system permits positive confirmation that functional changes seen after transplantation are due to the transplanted cells and not to background host myelination (2, 3). Electrophysiological studies from the md rat spinal cord have shown that while the amyelinated fibers ofthe md rat are capable of secure impulse conduction, they do so at -1/4 the conduction velocity of age-matched controls (14). We report here that myelination ofThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "adve...

Cell Therapy for Multiple Sclerosis

“…Although postmitotic oligodendrocytes have poor remyelinating capacity [123], their immediate progenitors exhibit greater mitotic, migratory, and regenerative properties in both genetic dysmyelinating and adult focal demyelinating models of disease [124][125][126][127]. Transplanted rodent OPCs myelinated nude axons and restored nerve conduction velocity to near normal values in the spinal cord of md rats [128], and canine OPCs repaired large brain areas in the sh pup [126].…”

Oligodendrocyte Fate after Spinal Cord Injury

“…Despite these characteristics, remyelination can restore axonal conduction velocity, as elegantly illustrated by Smith et al [47]. As a proof of principal, studies by the Duncan laboratory [48] bolstered the notion that remyelination restores function. They showed that remyelination by transplanted OLs in myelin-deficient animals restored conduction velocity to near normal.…”

“…Although a variety of transplant studies have been conducted with distinct sources and cell types in SCI models, we will highlight a few relevant studies here that focus on CNS stem-cell based transplants (for excellent reviews, see Enzmann et al [157], Coutts et al [158], and Kulbatski et al [159]). Early work by Utzschneider et al [48] served as proof of principal that transplantation of OLs in myelin-deficient animals would lead to remyelination and axon potential conduction velocity to near normal values. One of the first experiments to test transplantation from a therapeutic standpoint was conducted in an ethidium bromidedemyelinating lesion in which postnatally derived OPCs remyelinated spinal cord lesions [160].…”

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

“…The spinal cord at the site of cell transplant was removed and placed in a brain chamber. The site of engraftment and myelin made by the cells was visible by a naked-eye inspection [89], (Fig. 1), hence it was possible to place stimulating and recording electrodes over both myelinated and nonmyelinated areas of the spinal cord.…”

“…Areas with myelin repair showed a threefold increase in conduction velocity. Other parameters of normal conduction, such as frequency-response parameters were normal [89]. In the first study of node of Ranvier formation in shi previously noted [79], the authors recorded spinal cord-evoked potentials by stimulating and recording from the dorsal column of the thoracic spinal cord.…”