Mast cells can contribute to axon–glial dissociation and fibrosis in peripheral nerve

Abstract

Expression of the human epidermal growth factor receptor (EGFR) in murine Schwann cells results in loss of axon-Schwann cell interactions and collagen deposition, modeling peripheral nerve response to injury and tumorigenesis. Mast cells infiltrate nerves in all three situations. We show that mast cells are present in normal mouse peripheral nerve beginning at 4 weeks of age, and that the number of mast-cells in EGFR(+) nerves increases abruptly at 5-6 weeks of age as axons and Schwann cells dissociate. The increase in mast cell number is preceded and accompanied by elevated levels of mRNAs encoding the mast-cell chemoattractants Rantes, SCF and VEGF. Genetic ablation of mast cells and bone marrow reconstitution in W(41) x EGFR(+) mice indicate a role for mast cells in loss of axon-Schwann cell interactions and collagen deposition. Pharmacological stabilization of mast cells by disodium cromoglycate administration to EGFR(+) mice also diminished loss of axon-Schwann cell interaction. Together these three lines of evidence support the hypothesis that mast cells can contribute to alterations in peripheral nerves.

Characterization of Neurofibromas of the Skin and Spinal Roots in a Mouse Model

“…A follow-up study using reciprocal bone-marrow transplantation between Nf1 +/-and Nf1 +/+ mice provide evidence that an Nf1 +/-c-Kit expressing hematopoietic cell contributes strongly to the plexiform neurofibroma phenotype, independent of Cre-mediated recombination ). In contrast, recent studies have reported the generation of plexiform neurofibromas in a wildtype Nf1 environment (Wu et al 2008) and that wildtype mast cells can contribute to tumor formation (Monk et al 2007). With the data presented in this paper, we can now reconcile these seemingly disparate results, clarifying the role of the Nf1 +/-microenvironment in peripheral nerve sheath tumorigenesis.…”

“…Mast cells are unlikely contribute to the generation of Schwann cell pocket defects, as they are not present during this phase of peripheral nerve sheath tumor initiation. We cannot rule out the possibility that Nf1 +/+ or Nf1 +/-mast cells may contribute to loss of axon/glial interaction at P90; previous reports suggest this may indeed be the case (Monk et al 2007 Figure 3A). In contrast, the mutant P90 Nf1 -/-nerves consistently had elevated phospho-Erk and phospho-S6 levels ( Figure 3B).…”

“…Thus, plexiform neurofibroma initiation and progression can be separated into two distinct stages based off their dependency on the Nf1 +/-microenvironment. In this light, prior studies implicating that Nf1 +/+ mast cell contribute to plexiform neurofibroma initiation is no longer contradictory with the role of Nf1 +/-mast cells may play in progression (Monk et al 2007;Yang et al 2008).…”

Neurodynamic Mobilization Reduces Intraneural Fibrosis After Sciatic Crush Lesion in Rats

“…This could lead to an increase in blood flow and presence of collagen synthesizing cells 4 . However, if these phenomena are excessive, or collagen fibers deposited in a random manner at the site of the lesion, local fibrosis could occur 17 .…”

“…On one hand, mastocytes produce and release a variety of chemical mediators related to vascular proliferation and vasodilatation 3 . They also produce proteolytic enzymes responsible for the degradation of the basal membrane and extracellular matrix, which contribute to fibroblast activation and collagen deposition 4 . On the other hand, blood flow and angiogenesis help with tissue nutrition and create an adequate microenvironment for the repair process 5 .…”