Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination

Abstract

We have documented changes in the oligodendrocyte population during demyelinating insult to the adult CNS. Feeding of cuprizone to adult mice led to apoptotic death of mature oligodendrocytes followed by profound demyelination of the corpus callosum. A regenerative response was initiated even during active demyelination. Oligodendrocyte progenitors have begun to proliferate and then accumulate within the lesion. Many of these cells may have migrated from the sub‐ventricular zone and fornix before their accumulation in the demyelinating corpus callosum. The accumulation of differentiating oligodendrocyte progenitors was followed closely by the reappearance of mature oligodendrocytes and remyelination. Interestingly, an increase in IGF‐1 mRNA was detected at Week 3 through Week 7, suggesting potential involvement in remyelination. Other factors, however, such as PDGF, NT3, FGF, jagged, and notch remained unchanged. These results suggest that the mature oligodendroglial population depleted by apoptosis is replaced by a newly formed oligodendroglial population derived from progenitors; these accumulate and seem to differentiate during remyelination. J. Neurosci. Res. 61:251–262, 2000. © 2000 Wiley‐Liss, Inc.

Growth factor regulation of remyelination: behind the growing interest in endogenous cell repair of the CNS

“…Analysis of models of acute demyelination have been well suited for testing the capacity of growth factors to prevent oligodendrocyte cell death and subsequent demyelination [4,13,14]. During acute demyelination, OP cells proliferate to amplify the OP population several-fold and generate oligodendrocytes to repopulate lesioned areas [15,16]. Since transient episodes of acute demyelination have this typically robust OP response and extensive remyelination, such models are advantageous for testing growth factor manipulations that are predicted to impair spontaneous remyelination but may be less useful for testing modifications to promote remyelination [7,14,15,17].…”

“…In experimental models of demyelination in rodents, extensive remyelination requires proliferation of immature OP cells followed by differentiation into myelinating oligodendrocytes [15,16,22]. With repeated transient episodes of demyelination and sufficient time between individual episodes, the OP population can repeatedly generate new oligodendrocytes and regenerate the OP pool [6].…”

“…With cuprizone demyelination of the corpus callosum, toxicity is primarily within mature oligodendrocytes, presumably because of the metabolic load of maintaining the extensive myelin membranes [39]. During cuprizone treatment, OP populations proliferate both within the demyelinated areas of white matter and in the adjacent SVZ [15,29,37]. By contrast, demyelination models of lysolecithin or ethidium bromide injection have significant loss of OP cells within lesion areas [40,41].…”

Insulin-Like Growth Factor (IGF) Signaling through Type 1 IGF Receptor Plays an Important Role in Remyelination

“…Several of the signaling molecules that influence the migration, proliferation, and differentiation of oligodendrocyte progenitors are expressed within remyelinating lesions in the CNS (Redwine and Armstrong, 1998;Hinks and Franklin, 1999;Mason et al, 2000a). However, the factor(s) responsible for the recruitment and differentiation of these progenitors in vivo is not known.…”

“…IGF-1 is a survival factor for oligodendrocytes (Barres et al, 1993;Ye and D'Ercole, 1999;Mason et al, 2000b) and a differentiation factor for neonatal (McMorris and Dubois-Dalq, 1988;Mozell and McMorris, 1991) and adult (Mason and Goldman, 2002) oligodendrocyte progenitors in vitro. Its levels are elevated within demyelinating and remyelinating lesions in the adult CNS (Liu et al, 1994;Yao et al, 1995;Mason et al, 2000a). In addition, the inability of the adult CNS to remyelinate after a demyelinating lesion in interleukin-1␤Ϫ/Ϫ mice coincides with a significant reduction in IGF-1 expression (Mason et al, 2001a).…”