Cell Dedifferentiation and Proliferation

The distal part of an injured axon is degraded by a process called Wallerian degeneration. The mechanism of Wallerian degeneration is distinct from pathological neurodegenerative processes such as dying back from the target tissue or the pruning process observed during embryonic neurogenesis that matches the proper number of axons to their targets (Raff et al., 2002).

During Wallerian degeneration, axons and their myelin layers distal to the injury disintegrate over a period of several days. Myelin proteins are inhibitory to axon regeneration and must be removed from the endoneurial tubes (Fu and Gordon, 1997). Electron microscopic, metabolic labeling, and cell surface marker expression studies have shown that the Schwann cells degrade small bits of myelin, but that the bulk of the myelin is phagocytosed and degraded by macrophages that enter the nerve tubes (Goodrum and Bouldin, 1996) (figure 5.4). The resulting cholesterol and free fatty acids are complexed to apolipoprotein E within the macrophages to form lipoprotein particles. These particles are then released and taken up by Schwann cells via low-density lipoprotein (LDL) receptors, to be reused in myelin synthesis during axonal regeneration.

Apolipoprotein Receptors

remyelinating axon

FIGURE 5.4 Wallerian degeneration of axons and salvage pathway for re-myelination. Macrophages penetrate the basement membrane to phagocytose myelin debris. Within the macrophage, myelin phospholipids (PL) are hydrolyzed to free fatty acids (FFA). Up to half the FFA are re-incorporated into phospholipids. These phospholipids and all the cholesterol (CH) are complexed to apolipoprotein E (apoE) to form lipoprotein particles (LP) that are then taken up by Schwann cells via low-density lipoprotein receptors to be re-used for myelin synthesis.

remyelinating axon

FIGURE 5.4 Wallerian degeneration of axons and salvage pathway for re-myelination. Macrophages penetrate the basement membrane to phagocytose myelin debris. Within the macrophage, myelin phospholipids (PL) are hydrolyzed to free fatty acids (FFA). Up to half the FFA are re-incorporated into phospholipids. These phospholipids and all the cholesterol (CH) are complexed to apolipoprotein E (apoE) to form lipoprotein particles (LP) that are then taken up by Schwann cells via low-density lipoprotein receptors to be re-used for myelin synthesis.

Band Bungner
FIGURE 5.5 Dedifferentiated Schwan cells (DSC) proliferate on both sides of a crush injury to bridge the lesion. The cords of DSCs are called bands of Bungner (BB). Axons (A) sprout into the bands of Bungner of the individual endoneurial tubes. En = endoneurium, BM = basement membrane, M = myelin.

As their myelin is degraded, the Schwann cells dedifferentiate within the basement membrane to form cords of cells called the bands of Bungner (figure 5.5). They proliferate and migrate to form a continuous bridge across the lesion and down the length of the distal endoneurial tubes. Axotomized neurons, along with macrophages and platelets that have invaded the injury site, produce growth factors and cytokines that are mitogenic for Schwann cells (TABLE 5.1). Many of these molecules are the same ones responsible for the fibrosis of skin repair, such as FGF, PDGF, IL 1,2, and 6, TGF-P and IFN-y, as well as nerve-specific factors such as glial growth factor (GGF) (Fu and Gordon, 1997). When the gap in the nerve is too large to be bridged by dedifferentiating Schwann cells, fibroblasts enter the wound space and these same factors induce scar formation, preventing regeneration.

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