Schwann cell proliferation and migration during paranodal demyelination

Abstract

This study examined Schwann cell behavior during paranodal demyelination induced by beta,beta'-iminodipropionitrile (IDPN). The stimuli for Schwann cell proliferation, extensively studied in vitro, are less well understood in vivo. Most in vivo systems previously used to examine Schwann cell proliferation in disease are dominated by loss of internodal myelin sheaths. As used in this study, IDPN administration produces neurofilamentous axonal swellings and paranodal demyelination, without segmental demyelination or fiber degeneration. We asked whether Schwann cells would proliferate following the restricted paranodal demyelination that accompanies the axonal swellings, and if so what the sources and distributions of new Schwann cells might be. IDPN was given as a single large dose (2 ml/kg) to 21-d-old rats. Neurofilamentous axonal swellings formed in the proximal regions of motor axons, reaching their greatest enlargement in the root exit zone 8 d after IDPN administration. These swellings subsequently migrated distally down the nerves at rates approaching 1 mm/d. The axonal enlargement was consistently associated with displacement of the myelin sheath attachment sites into internodal regions, and consequent paranodal demyelination. This stage was associated with perikaryal changes, including nucleolar enlargement, "girdling" of the perikaryon, and formation of attenuated stalks separating the perinuclear region from the external cytoplasmic collar. Schwann cells proliferated abundantly during this stage. Daughter Schwann cells migrated within the endoneurial space (outside the nerve fiber basal laminae) to overlie the demyelinated paranodes of swollen nerve fibers. In these regions, local proliferation of Schwann cells continued, resulting in large paranodal clusters of Schwann cells. As the axonal calibers subsequently returned to normal, the outermost myelin lamellae of the original internodes returned to their paranodal attachment sites and the supernumerary Schwann cells disappeared. Formation of short internodes, segmental demyelination, and nerve fiber loss were rare phenomena. These results indicate that paranodal demyelination is a sufficient stimulus to excite abundant Schwann cell proliferation; neither internodal demyelination nor myelin breakdown is a necessary stimulus for mitosis. The 3H-thymidine incorporation studies indicated that the sources of new Schwann cells included markedly increased division of the Schwann cells of unmyelinated fibers and, as they formed, supernumerary Schwann cells. In addition, there were rare examples of 3H-thymidine incorporation by Schwann cells associated with myelinated nerve fibers.(ABSTRACT TRUNCATED AT 400 WORDS)

Biology and pathology of nonmyelinating Schwann cells

“…Systemic administration of IDPN results in impaired neurofilament transport and the formation of large neurofilamentous axonal swellings beginning just beyond the initial segment and occupying the first several internodes (Griffin et al, 1987) (see Fig. 4).…”

Degeneration of Myelinated Efferent Fibers Prompts Mitosis in Remak Schwann Cells of Uninjured C-Fiber Afferents

“…Previous studies of nerves undergoing demyelination reached similar conclusions. In the models of lysophosphatidyl choline application (Griffin et al, 1990) and 3,3-iminodipropionitrile (Griffin et al, 1987) administration, internodal and paranodal demyelination, respectively, were associated with entry of RSCs into the cell cycle. In those models, it was difficult to exclude a degree of injury to the axons of unmyelinated fibers.…”

“…Such an observation would suggest that diffusible mitogens, capable of signaling Schwann cells that neighbor degenerating axons, might be important. Previous studies of demyelinating nerve injury showed division of Schwann cells associated with uninjured Remak bundles, but a direct effect on Remak Schwann cells could not be excluded (Griffin et al, 1987(Griffin et al, , 1990. In this study, we used ventral rhizotomy as a model of selective nerve injury in the rat.…”

“…Other Schwann cells do not produce myelin but continue to ensheath one or more axons in unmyelinated nerve fiber (Remak) bundles (Murinson and Griffin, 2004). In the normal adult nerve, there is no evidence that myelinating Schwann cells (MSCs) enter cell cycle, and the division of nonmyelinating (Remak) Schwann cells is infrequent (Griffin et al, 1987(Griffin et al, , 1990. Nerve disease and injury, including nerve transection and demyelination, prompt Schwann cells to enter cell cycle (Friede and Johnstone, 1967;Pellegrino and Spencer, 1985;Griffin et al, 1987Griffin et al, , 1990Oaklander et al, 1987b;Cheng and Zochodne, 2002).…”

“…In the normal adult nerve, there is no evidence that myelinating Schwann cells (MSCs) enter cell cycle, and the division of nonmyelinating (Remak) Schwann cells is infrequent (Griffin et al, 1987(Griffin et al, , 1990. Nerve disease and injury, including nerve transection and demyelination, prompt Schwann cells to enter cell cycle (Friede and Johnstone, 1967;Pellegrino and Spencer, 1985;Griffin et al, 1987Griffin et al, , 1990Oaklander et al, 1987b;Cheng and Zochodne, 2002). The factors that signal this proliferation are not fully understood (Pellegrino et al, 1986;Oaklander and Spencer, 1988;Clemence et al, 1989).…”