gms | German Medical Science

Objective: Neuromas are pathologic nerve distensions caused by a nerve’s response to trauma. Following traumatic peripheral nerve injury (PNI), sprouting axons attempt to cross the injury site as long as scar tissue, a gap or lacking axonal guidance do not counteract sprouting. If target-oriented sprouting is prevented, a neuroma will form. Following PNI, endoneurial cells provide axonal guidance for successful regeneration, while perineurial cells form a diffusion-barrier via tight-junctions to provide a physiologically restricted intra-fascicular space. The cellular communication between those perineurial cells as well as the exchange of small molecules is mediated via connexins (Cx26 and Cx43). However, the cellular and molecular changes following PNI have not yet been resolved for human nerve.

Methods: The endo- and perineurial cells were detected by immunohistochemistry and immuno-electron microscopy using antibodies directed against CD34 (endoneurial fibroblast like cells, EFLCs) and the Glucose-Transporter 1 (Glut1, perineurial cells). Furthermore, the formation of tight-junctions and the expression of connexins in endo- and perineurial cells was analyzed using antibodies directed against the tight junctional marker protein Claudin1 as well as Cx26 and Cx43 in six human traumatic neuromas.

Results: Following PNI, axons as well as the endo- and perineurial structures were disrupted and mini-fascicles of regenerating axons were detectable in the neuromatous tissue. In the proximal neuroma, mini-fascicles were ensheathed by a single layer of CD34 expressing EFLCs and surrounded by a reduced number of Glut1 positive perineurial cells, compared to fascicles of an intact nerve. Those perineurial cells were expressing a highly reduced amount of Claudin1, Cx26 and Cx43 protein. In the distal neuroma segment as well as in the degenerated end, located distal to the injury site, endo- and perineurial ensheathment of the regenerating axons was absent. The immunhistological labeling revealed scattered endo- and perineural cells in the distal and degenerated neuroma segments. However, no tight-junction formation and a highly decreased connexin expression was observed in those cells.

Conclusion: Unsuccessful axonal regeneration might be related to the lack of endoneurial as well as perineurial structures in the distal neuroma and the degenerated end, which results in the disruption of the perineurial nerve barrier and the axonal guidance to the target organ.