Proliferative capacity of oligodendrocytes in the demyelinating twitcher spinal cord

The proliferative capacity of oligodendrocytes was investigated in the spinal white matter of the twitcher mouse, a murine model of a genetic demyelinating disease globoid cell leukodystrophy (GLD), in which degeneration of oligodendrocytes due to metabolic perturbation has been well documented. In normal mice at 30 and 45 days of age, proliferating cells labeled with 5-bromo-2'-deoxyuridine (BrdU) were scarce, and the majority of BrdU-labeled cells did not immunostain with antibodies for oligodendrocytes, astrocytes, or microglia/macrophages. Only a few cells with markers for oligodendrocytes, carbonic anhydrase (CA), or the Pi form of glutathione-S-transferase (Pi), were labeled with BrdU. In the twitcher spinal cord, total numbers of BrdU-labeled cells were almost 6 times that of the normal littermate mice at 30 days of age, and 28 times at 45 days of age. However, this increase was largely due to an increase of cells labeled with F4/80, a marker for the microglia/macrophages. CA or Pi positive cells only constituted less than 10% of all labeled cells. With progression of demyelination from 30-45 days, total numbers of CA positive or Pi positive oligodendrocytes decreased, but percentages of cells double-labeled with BrdU and CA or Pi remained fairly constant. The results indicated that oligodendrocytes proliferated, to some extent, in the twitcher despite the genetic metabolic defect, and their decrease in number with progression of disease was not due to declined proliferation but rather cellular degeneration as the result of an intrinsic metabolic perturbation.