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Abstract
Schwann cells exhibit a high degree of plasticity in adult peripheral nerves after mechanical injury; they have, therefore, been implicated in promoting nerve regeneration. However, Schwann cell behavior after ischemic injury has not yet been elucidated. To determine how Schwann cell plasticity may contribute to recovery from ischemic neuropathy, we used a rat model in which ischemia was induced in the tibial nerve by a 5-hour occlusion of the supplying arteries. Proliferation of immature Schwann cells that emerged in the injured nerve was evaluated by double immunostaining for the p75 neurotrophin receptor and proliferating cell nuclear antigen. The number of proliferating cell nuclear antigen/p75 neurotrophin receptor doublepositive cells increased significantly in 1 to 2 weeks after ischemia and subsequently decreased by 4 weeks. During this time, the postmitotic Schwann cells differentiated into mature cells, as demonstrated with bromodeoxyuridine incorporation, which facilitated axon guidance and subsequent axon remyelination. These results suggest the emergence and proliferation of immature Schwann cells that contribute to nerve regeneration after ischemic injury. The manipulation of this population of proliferating immature Schwann cells may be a useful strategy for treating ischemic peripheral neuropathy.
Key Words: Cell dedifferentiation, Cell division, Myelin, Nerve regeneration, Neuroglia, Neurotrophin receptor p75, Peripheral nerve ischemia, Schwann cells.
INTRODUCTION
Ischemic peripheral neuropathy is a consequence of interruption of the blood supply resulting in axon disruption (1). Inadequate regeneration then results in irreversible neurologic dysfunction of the extremities. Nerve ischemia related to vascular abnormalities occurs in a variety of pathologic conditions. For example, capillary basement membrane thickening and endothelial cell hyperplasia are well-recognized components of the pathogenesis of diabetic neuropathy (2). Ischemic neuropathy associated with primary vasculitides and collagen vascular diseases is caused by occlusion of blood vessels due to inflammation in the walls of the vasa nervorum (3), and iatrogenic arterial occlusion after surgical procedures may result in ischemic monomelic neuropathy and critical limb ischemia (4). Thus, the pathophysiology of ischemic neuropathy due to various acquired conditions needs to be elucidated. Moreover, few specific therapeutic options have been established to alleviate ischemic nerve degeneration or to promote nerve regeneration in humans.
Animal models of ischemic neuropathy have provided insights into the mechanisms of nerve degeneration and regeneration after ischemic damage (5-18). After the arterial supply to...