The role of non-resident cells in Wallerian degeneration

Abstract

Wallerian degeneration was studied in the phrenic or sciatic nerves of mice following transplantation into Millipore diffusion chambers of 0.22 micron pore size which were implanted in the peritoneal cavity and kept for up to eight weeks. This method positively eliminates the access of nonresident cells to the tissue, at the same time providing proper conditions for tissue survival. Such nerves showed no proliferation of Schwann cells and no evidence for their active role in the removal or digestion of myelin. Schwann cells rejected their sheaths and the latter persisted for weeks, leading either to sheath distension (the sheath becoming wider and thinner) or to collapse (the sheath becoming thicker, collapsing upon the empty axis cylinder). The outer envelope of Schwann cytoplasm separated into pseudopodia rich in microtubules. Sheath rejection led to a slow decay of the myelin in the absence of active phagocytosis. There was profuse fibroblastic proliferation from the epineurium and perineurium, from which cells migrated into the chambers developing fatty change. No evidence was found to link the fatty change in fibroblasts to sheath decay. Diffusion chambers of 5.0 micron pore size were invaded by leukocytes and monocytes. Nerves kept in such chambers showed active phagocytosis of myelin leading to its removal, similar to Wallerian degeneration in situ. Phagocytes were shown to attack selectively the rejected myelin sheaths, distinguishing the latter from the surviving Schwann cells, even though both structures derive from the same cell. The activity of phagocytes in digesting myelin was mediated by a signal which diminished in intensity with time; there was very little active phagocytosis of myelin in nerves that had been predegenerated in 0.22 micron pore chambers. Various modifications of the experiment, including studies with co-cultured peritoneal macrophages or bone marrow, indicate a need for additional activating factors to induce myelin phagocytosis.

Pancreatitis-Associated Protein-III Is a Novel Macrophage Chemoattractant Implicated in Nerve Regeneration

“…In injured nerves, infiltration of neutrophils is hardly observed, whereas a substantial influx of macrophages into degenerating nerves is seen at 2-3 d after nerve injury (Ramó n y Cajal, 1928;Beuche and Friede, 1984;Perry et al, 1987;Stoll et al, 1989). These findings strongly suggest that macrophage chemoattractants are released from injured nerves, from either the injured nerve tips or Schwann cells.…”

“…Wallerian degeneration is accompanied by orchestrated cellular responses in the injured neurons, dedifferentiated Schwann cells, and cells involved in immune systems (Scherer and Salzer, 2001). Among such cellular responses, the most striking is macrophage invasion into the degenerating nerves, mainly by circulating hematogenous monocytic cells (Beuche and Friede, 1984). Multiple beneficial roles of the invading macrophages appear to contribute to Wallerian degeneration and subsequent axonal regeneration (Hughes and Perry, 2000).…”

Effect of local application of transforming growth factor–β at the nerve repair site following chronic axotomy and denervation on the expression of regeneration-associated genes

“…Schwann cells that are not involved in myelinating axons and are nevertheless in an activated state undergo apoptosis and are cleared by macrophages. 3,21,45 The activated macrophages are attracted to factors released from the cellular debris produced by the presence of active apoptotic cells, such that as long as apoptotic cells are present, activated macrophages will be also.…”

“…20 Thus, it appears that Schwann cells can maintain their growth-supportive phenotype only in the presence of active Wallerian degeneration. 12,28 Macrophages' key roles in Wallerian degeneration include removing debris 3 and producing cytokines that stimulate production of neurotrophic factors by nonneuronal cells of the distal nerve stumps, 8,10,12,21 including transforming growth factor-b (TGF-b). After nerve injury, TGF-b is secreted into the injured nerves by invading macrophages 2 and by Schwann cells themselves.…”

Inflammatory response of the spinal cord to multiple episodes of blood-brain barrier disruption and toxic demyelination in Wistar rats

“…Fast activation of mononuclear phagocytes is characteristic of primary demyelination. It is likely that the attracting signal for macrophage entry is specific and transient (11). This would explain the persistence of myelin debris within the extracellular space of some lesions, when adequate macrophage activation did not take place after oligodendrocyte death.…”