Schwann cell mitosis response to regenerating peripheral axons in vivo
Schwann cell mitosis has been demonstrated in chronically denervated cat tibial nerves re-innervated by axons regenerating from the proximal stump of a coapted peroneal nerve. Thymidine incorporation rose above baseline levels at the axon front, with no detectable increase in more distal regions occupied by denervated Schwann cells. Schwann cells therefore enter S phase upon the arrival of a regenerating axon in vivo as previously described in tissue culture. Intraneural treatment of the denervated distal stump with Mitomycin C prior to re-innervation delayed the subsequent appearance of myelin formation. This supports the notion that axonally stimulated division of Schwann cells is a prerequisite for myelination during nerve regeneration. Axonal advancement was also retarded by drug treatment, possibly because of a reduced level of trophic support provided by the compromised Schwann cells. A comparable absence of myelin and poor re-innervation was found in chemically untreated distal stumps that had been maintained in the denervated state for prolonged periods when Schwann cell columns are known to undergo progressive atrophy. These observations suggest that nerve repair should be delayed for limited periods if efficacious regeneration is desired.
[Show abstract] [Hide abstract] ABSTRACT: Peripheral nerve injury has significant societal and economic impact. Current gold standard treatment for severe peripheral nerve injury is autografting, which requires the sacrifice of a donor nerve. Despite best practices, recovery from severe peripheral nerve injuries is often suboptimal. Pluripotent stem cells, bone marrow mesenchymal cells, adipose-derived stem cells, skin-derived precursor cells, and hair follicle pluripotent stem cells can be induced into Schwann cells and/or Schwann cell-like phenotypes; when administered in combination with artificial nerve graft conduits, these cells improve morphological and functional recovery in mouse, rat, and primate models of transecting peripheral nerve injury. Questions regarding survival, differentiation, and safety of cell-based therapy remain to be answered, and no cell-based therapies have yet translated to humans, but if current trends indicate potential, stem cell-based therapy is promising.0Comments 0Citations
- "Even with meticulous microsurgical technique, repair often results in nonspecific and incomplete regeneration (Lago, Rodríguez, Guzmán, Jaramillo, & Navarro, 2007; Navarro, Vivó, & Valero-Cabré, 2007; Nichols et al., 2004; Shieh, Lee, & Chiu, 2007) because functional recovery requires that severed axons accurately reconnect with the preinjury number and size of motor units (Kubo et al., 2009). Advances in microsurgical technique and neuroscience have failed to address the extensive cell death that occurs in dorsal rootthe site of injury fail to maintain a growth-supportive environment (Pellegrino & Spencer, 1985; Taniuchi, Clark, Schweitzer, & Johnson, 1988; Weinberg & Spencer, 1978). With time, cells in the distal nerve stump progressively lose their ability to support axonal regrowth (Fu & Gordon, 1995). "
[Show abstract] [Hide abstract] ABSTRACT: Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.0Comments 25Citations
- "Nerve injury and repair is associated with two phases of Schwann cell proliferation: the first phase is due to loss of axonal contact and peaks around 3 days post-injury (Bradley and Asbury, 1970; Stoll et al., 1989; Carroll et al., 1997; Stoll and Muller, 1999; Griffin and Thompson, 2008). The second phase of proliferation occurs as axons enter the denervated nerve stump (Pellegrino and Spencer, 1985). Because of the role of NRG1 in Schwann cell proliferation during development (Dong et al., 1995; Parkinson et al., 2004; Perlin et al., 2011) and in the post-natal period (Chen et al., 2003), we investigated the role of NRG1 in modulating Schwann cell proliferation following injury. "
[Show abstract] [Hide abstract] ABSTRACT: Animal models of nerve compression, crush, and transection injuries of peripheral nerves have been subject to extensive study in order to understand the mechanisms of injury and axon regeneration and to investigate methods to promote axon regeneration and improve functional outcomes following nerve injury. Six outcome measures of regenerative success including axon and neuron counts, muscle and motor unit contractile forces, and behavior are reviewed in the context of nerve injury types, crush, transection and nerve repair by direct coaptation, or transection and repair via a nerve graft or conduit. The measures are evaluated for sciatic, tibial, common peroneal, femoral, single nerve branches such as the soleus nerve, and facial nerves. Their validity is discussed in the context of study objectives and the nerve branch. The case is made that outcome measures of axon counts and muscle contractile forces may be valid during the early phases of axon regeneration when regenerating sprouts emerge asynchronously from the proximal nerve stump and regenerate towards their denervated targets. However, care must be taken especially when experimental interventions differentially affect how many neurons regenerate axons and the number of axons per neuron that sprout from the proximal nerve stumps. Examples of erroneous conclusions are given to illustrate the need for researchers to ensure that the appropriate outcome measures are used in the evaluation of the success of peripheral nerve regeneration.0Comments 69Citations
- "a Note that the total numbers of studies for each experimental nerve injury are not necessarily the sum of individual measures because more than one measure was frequently used in the studies. tion (Pellegrino and Spencer, 1985; Birchmeier and Nave, 2008). "