Limits...
Function-triggering antibodies to the adhesion molecule L1 enhance recovery after injury of the adult mouse femoral nerve.

Guseva D, Loers G, Schachner M - PLoS ONE (2014)

Bottom Line: The present study was undertaken to investigate whether the monoclonal L1 antibody 557 that triggers beneficial L1 functions in vitro would trigger these also in femoral nerve repair.This improved recovery was associated with attenuated motoneuron loss, remyelination and improved precision of preferential motor reinnervation.We suggest that function-triggering L1 antibodies applied to the lesion site at the time of injury over a limited time period will not only be beneficial in peripheral, but also central nervous system regeneration.

View Article: PubMed Central - PubMed

Affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.

ABSTRACT
L1 is among the few adhesion molecules that favors repair after trauma in the adult central nervous system of vertebrates by promoting neuritogenesis and neuronal survival, among other beneficial features. In the peripheral nervous system, L1 is up-regulated in Schwann cells and regrowing axons after nerve damage, but the functional consequences of this expression remain unclear. Our previous study of L1-deficient mice in a femoral nerve injury model showed an unexpected improved functional recovery, attenuated motoneuronal cell death, and enhanced Schwann cell proliferation, being attributed to the persistent synthesis of neurotrophic factors. On the other hand, transgenic mice over-expressing L1 in neurons led to improved remyelination, but not improved functional recovery. The present study was undertaken to investigate whether the monoclonal L1 antibody 557 that triggers beneficial L1 functions in vitro would trigger these also in femoral nerve repair. We analyzed femoral nerve regeneration in C57BL/6J mice that received this antibody in a hydrogel filled conduit connecting the cut and sutured nerve before its bifurcation, leading to short-term release of antibody by diffusion. Video-based quantitative analysis of motor functions showed improved recovery when compared to mice treated with conduits containing PBS in the hydrogel scaffold, as a vehicle control. This improved recovery was associated with attenuated motoneuron loss, remyelination and improved precision of preferential motor reinnervation. We suggest that function-triggering L1 antibodies applied to the lesion site at the time of injury over a limited time period will not only be beneficial in peripheral, but also central nervous system regeneration.

Show MeSH

Related in: MedlinePlus

Analysis of myelination in regenerated femoral nerves in mice treated with L1 Ab 557 or PBS in the conduits applied to the transected nerves.(A) Representative images of the motor and sensory nerve branches from L1 Ab 557 or PBS treated mice. (B) Mean orthogonal diameters of the axon (black arrows) and of the nerve fiber (white arrows) were measured and the degree of myelination was estimated by the ratio of axon to fiber diameter (g-ratio). (C) Normalized frequency distributions of g-ratios in regenerated motor and sensory nerve branches. Regenerated nerves were studied 12 weeks after injury. Ten mice per group were analyzed. The shift in distributions of g-ratios to the left in the group treated with L1 Ab 557 in the sensory nerve shows better myelination compared to the group of animals treated with PBS (p<0.05, Kolmogorov-Smirnov test).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4231121&req=5

pone-0112984-g004: Analysis of myelination in regenerated femoral nerves in mice treated with L1 Ab 557 or PBS in the conduits applied to the transected nerves.(A) Representative images of the motor and sensory nerve branches from L1 Ab 557 or PBS treated mice. (B) Mean orthogonal diameters of the axon (black arrows) and of the nerve fiber (white arrows) were measured and the degree of myelination was estimated by the ratio of axon to fiber diameter (g-ratio). (C) Normalized frequency distributions of g-ratios in regenerated motor and sensory nerve branches. Regenerated nerves were studied 12 weeks after injury. Ten mice per group were analyzed. The shift in distributions of g-ratios to the left in the group treated with L1 Ab 557 in the sensory nerve shows better myelination compared to the group of animals treated with PBS (p<0.05, Kolmogorov-Smirnov test).

Mentions: We next analyzed non-injured and regenerated nerves histologically to assess axonal numbers, axonal diameters and degree of myelination 12 weeks after injury. In both motor and sensory femoral nerve branches, the total number of myelinated axons was similar in both experimental groups compared with non-injured mice (Fig. 3A and B). However, myelin thickness in regenerated nerves was higher in the sensory branches of mice treated with L1 Ab 557 than in mice treated with PBS, as assessed by g-ratio (p<0.05, Kolmogorov-Smirnov test, Fig. 4A–C). Interestingly, the frequency distribution of axonal diameters was shifted towards higher values only in sensory branches in mice treated with L1 Ab 557 (p<0.05, Kolmogorov-Smirnov test) indicating that axons had larger diameters and more myelin compared PBS treated control mice (Fig. 5).


Function-triggering antibodies to the adhesion molecule L1 enhance recovery after injury of the adult mouse femoral nerve.

Guseva D, Loers G, Schachner M - PLoS ONE (2014)

Analysis of myelination in regenerated femoral nerves in mice treated with L1 Ab 557 or PBS in the conduits applied to the transected nerves.(A) Representative images of the motor and sensory nerve branches from L1 Ab 557 or PBS treated mice. (B) Mean orthogonal diameters of the axon (black arrows) and of the nerve fiber (white arrows) were measured and the degree of myelination was estimated by the ratio of axon to fiber diameter (g-ratio). (C) Normalized frequency distributions of g-ratios in regenerated motor and sensory nerve branches. Regenerated nerves were studied 12 weeks after injury. Ten mice per group were analyzed. The shift in distributions of g-ratios to the left in the group treated with L1 Ab 557 in the sensory nerve shows better myelination compared to the group of animals treated with PBS (p<0.05, Kolmogorov-Smirnov test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231121&req=5

pone-0112984-g004: Analysis of myelination in regenerated femoral nerves in mice treated with L1 Ab 557 or PBS in the conduits applied to the transected nerves.(A) Representative images of the motor and sensory nerve branches from L1 Ab 557 or PBS treated mice. (B) Mean orthogonal diameters of the axon (black arrows) and of the nerve fiber (white arrows) were measured and the degree of myelination was estimated by the ratio of axon to fiber diameter (g-ratio). (C) Normalized frequency distributions of g-ratios in regenerated motor and sensory nerve branches. Regenerated nerves were studied 12 weeks after injury. Ten mice per group were analyzed. The shift in distributions of g-ratios to the left in the group treated with L1 Ab 557 in the sensory nerve shows better myelination compared to the group of animals treated with PBS (p<0.05, Kolmogorov-Smirnov test).
Mentions: We next analyzed non-injured and regenerated nerves histologically to assess axonal numbers, axonal diameters and degree of myelination 12 weeks after injury. In both motor and sensory femoral nerve branches, the total number of myelinated axons was similar in both experimental groups compared with non-injured mice (Fig. 3A and B). However, myelin thickness in regenerated nerves was higher in the sensory branches of mice treated with L1 Ab 557 than in mice treated with PBS, as assessed by g-ratio (p<0.05, Kolmogorov-Smirnov test, Fig. 4A–C). Interestingly, the frequency distribution of axonal diameters was shifted towards higher values only in sensory branches in mice treated with L1 Ab 557 (p<0.05, Kolmogorov-Smirnov test) indicating that axons had larger diameters and more myelin compared PBS treated control mice (Fig. 5).

Bottom Line: The present study was undertaken to investigate whether the monoclonal L1 antibody 557 that triggers beneficial L1 functions in vitro would trigger these also in femoral nerve repair.This improved recovery was associated with attenuated motoneuron loss, remyelination and improved precision of preferential motor reinnervation.We suggest that function-triggering L1 antibodies applied to the lesion site at the time of injury over a limited time period will not only be beneficial in peripheral, but also central nervous system regeneration.

View Article: PubMed Central - PubMed

Affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.

ABSTRACT
L1 is among the few adhesion molecules that favors repair after trauma in the adult central nervous system of vertebrates by promoting neuritogenesis and neuronal survival, among other beneficial features. In the peripheral nervous system, L1 is up-regulated in Schwann cells and regrowing axons after nerve damage, but the functional consequences of this expression remain unclear. Our previous study of L1-deficient mice in a femoral nerve injury model showed an unexpected improved functional recovery, attenuated motoneuronal cell death, and enhanced Schwann cell proliferation, being attributed to the persistent synthesis of neurotrophic factors. On the other hand, transgenic mice over-expressing L1 in neurons led to improved remyelination, but not improved functional recovery. The present study was undertaken to investigate whether the monoclonal L1 antibody 557 that triggers beneficial L1 functions in vitro would trigger these also in femoral nerve repair. We analyzed femoral nerve regeneration in C57BL/6J mice that received this antibody in a hydrogel filled conduit connecting the cut and sutured nerve before its bifurcation, leading to short-term release of antibody by diffusion. Video-based quantitative analysis of motor functions showed improved recovery when compared to mice treated with conduits containing PBS in the hydrogel scaffold, as a vehicle control. This improved recovery was associated with attenuated motoneuron loss, remyelination and improved precision of preferential motor reinnervation. We suggest that function-triggering L1 antibodies applied to the lesion site at the time of injury over a limited time period will not only be beneficial in peripheral, but also central nervous system regeneration.

Show MeSH
Related in: MedlinePlus