Leukemia inhibitory factor enhances the regeneration of transected rat sciatic nerve and the function of reinnervated muscle

Abstract

The cytokine leukemia inhibitory factor (LIF) favors the survival and growth of axons in vitro and in vivo. Fibronectin has been shown to enhance nerve regeneration when added in combination with various growth factors including LIF. The goal of this study was to evaluate the effect of LIF plus fibronectin on the regeneration of transected nerve and functional recovery of reinnervated skeletal muscle, in one experimental model of peripheral nerve repair, at two recovery times. The rat sciatic nerve was cut at mid‐thigh level and a silicone cuff containing either saline (control), LIF, or LIF plus fibronectin (L + F) was used to bridge the proximal and distal nerve stumps leaving a 1 cm gap between them. Rats were then explored at 6 or 12 weeks following the initial surgery. Regenerating nerves were assessed by measuring the diameter of myelinated axons, conduction velocity, and number of myelinated fibers. Muscle reinnervation was assessed by measuring muscle mass, force of contraction, and histologically for changes in muscle fiber type (type I and type II). In this report we demonstrate that at 6 weeks there were significant increases in 1) nerve conduction velocity, 2) myelinated axon diameter, and 3) number of myelinated axons over that of control (saline‐treated) animals. Both LIF groups demonstrated a shift in type II muscle fiber area compared to saline‐treated controls, with the L + F group having a significant increase in muscle mass. At 12 weeks there was an improved recovery over and above that demonstrated at 6 weeks. Muscle mass was 65% and 42% greater than control for LIF and L + F, respectively. Force of contraction, conduction velocity, myelinated fiber number, and diameter were also significantly greater for both LIF‐ and L + F‐ treated rats than saline‐treated rats. These results demonstrate that LIF significantly improves the regeneration of damaged peripheral nerves and the preservation of muscle viability, resulting in greatly enhanced recovery of skeletal muscle function. J. Neurosci. Res. 47:208–215, 1997. © 1997 Wiley‐Liss, Inc.

Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence

“…Return of muscle weight following peripheral nerve injury and muscle denervation is a corollary to functional recovery (Akassoglou et al, 2000; Aydin et al, 2004; Brown et al, 2002; Haase et al, 2003; Kobayashi et al, 1997; Lewin et al, 1997; Newman et al, 1996; Sterne et al, 1997; Terris et al, 1999; Tham et al, 1997). Measurements of EDL muscle mass were used to assess the amount of muscle atrophy and recovery due to sciatic nerve injury and muscle regeneration following reinnervation.…”

Expression of Leukemia Inhibitory Factor in Human Nerve following Injury

“…Although LIF is expressed at high levels after nerve injury, animal experiments have shown that further increase in the local concentration of LIF at the site of injury increases the survival and number of regenerating axons and aids the recovery of function in muscles supplied by the injured nerve (Dowsing et al, 2000;Tham et al, 1997). The similarity between the level of LIF found in humans and experimental injury suggests that local application of LIF, preferably in a slow-release form, might have similar beneficial effects after injury to human peripheral nerves, where recovery is much less rapid and functionally useful than in smaller animals.…”

Leukaemia inhibitory factor increases myoblast replication and survival and affects extracellular matrix production: combined in vivo and in vitro studies in post-natal skeletal muscle

“…Furthermore, in vivo, LIF is up-regulated in diseased and injured muscle (Barnard et al 1994;Kurek et al 1996a) and after sciatic nerve transection (Kurek et al 1996a). Exogenous LIF enhances skeletal muscle regeneration after crush injury and in the mdx mouse model of Duchenne muscular dystrophy (Kurek et al 1996b and the regeneration of transected peripheral nerve (Tham et al 1997). LIF slows the rate of degeneration in mdx diaphragm; it has been suggested that this may be the result of a strengthening of the cell membrane around myofibres and interaction with adjacent ECM (Austin et al 2000).…”