Progressive dysfunction of twitcher Schwann cells is evaluated better in vitro than in vivo.

The twitcher mutant (twi/twi) is an authentic murine model of globoid cell leukodystrophy, a genetic demyelinating disorder, where normally formed myelin degenerates due to a metabolic perturbation of myelin forming cells. We investigated the rate of Schwann cell proliferation in vivo and in vitro using thymidine autoradiography to evaluate cellular function of homozygous twitcher (twi/twi), and heterozygous (+/twi) and normal littermate (+/+) mice. At day 10 prior to onset of demyelination in twi/twi, the thymidine uptake by Schwann cells from sciatic nerves was similar regardless of genotype. In +/twi or +/+, the rate of proliferation in sciatic nerves sharply declined after day 10 and remained low at day 20 and thereafter. In contrast, in twi/twi nerve, in which myelin degeneration became progressively severe after day 10, Schwann cell proliferation persisted. Reflecting the in vivo status of Schwann cells as described by Clemence et al., thymidine uptake in vitro by Schwann cells from older twi/twi mice was transiently higher for the first 24 h in culture. When the rate of proliferation was determined for Schwann cells 1 to 8 days in vitro (DIV), twi/twi Schwann cells proliferated generally less than that of +/twi or +/+ and the rate progressively declined with age. The results of this study suggest that progressive dysfunction of twi/twi Schwann cells is better demonstrated in vitro than in vivo. We suggest that in vitro kinetic studies would provide useful methodology to evaluate the Schwann cell function in genetic or hereditary neuropathies in humans, in which intrinsic Schwann cell dysfunction is suspected as cause of demyelination and contribute to the understanding of their pathogenesis.