Semaphorin 3A Inhibits Nerve Regeneration During Early Stage after Inferior Alveolar Nerve Transection

Abstract

Neuroma formation at sites of injury can impair peripheral nerve regeneration. Although the involvement of semaphorin 3A has been suggested in neuroma formation, this detailed process after injury is not fully understood. This study was therefore undertaken to examine the effects of semaphorin 3A on peripheral nerve regeneration during the early stage after injury. Immunohistochemistry for semaphorin 3A and PGP9.5, a general neuronal marker, was carried out for clarify chronological changes in their expressions after transection of the mouse inferior alveolar nerve thorough postoperative days 1 to 7. At postoperative day 1, the proximal stump of the damaged IAN exhibited semaphorin 3A, while the distal stump lacked any immunoreactivity. From this day on, its expression lessened, ultimately disappearing completely in all regions of the transected inferior alveolar nerve. A local administration of an antibody to semaphorin 3A into the nerve transection site at postoperative day 3 inhibited axon sprouting at the injury site. This antibody injection increased the number of trigeminal ganglion neurons labeled with DiI (paired t-test, p < 0.05). Immunoreactivity of the semaphorin 3A receptor, neuropilin-1, was also detected at the proximal stump at postoperative day 1. These results suggest that nerve injury initiates semaphorin 3A production in ganglion neurons, which is then delivered through the nerve fibers to the proximal end, thereby contributes to the inhibition of axonal sprouting from the proximal region of injured nerves in the distal direction. To our knowledge, this is the first report to reveal the involvement of Sema3A in the nerve regeneration process at its early stage.

Sensory nerve‐deficient microenvironment impairs tooth homeostasis by inducing apoptosis of dental pulp stem cells

“…The process of nerve navigation during tooth development is strictly regulated by signalling networks, such as semaphorin 3A, 40 TGF‐β 41 and activin signalling, 42 and closely associated with tooth morphogenesis. Recent studies illuminate that in mice incisor, sensory nerve fibres secrete sonic hedgehog protein to activate Gli1 + cells, which is a critical subpopulation of MSCs differentiating into odontoblasts and pulp cells 5 .…”

The role of Semaphorin 3A in oral diseases

“…Regarding nerve regeneration, a study has shown that SEMA3A inhibits the regeneration progress after inferior alveolar nerve transection (Kanemaru et al, 2019). Following an injury to the inferior alveolar nerve, ganglia produce SEMA3A, which is transmitted through nerve fibers and inhibits nerve regeneration to the distal end (Kanemaru et al, 2019). This characteristic also holds bioengineering significance.…”

Crosstalk between Bone and Nerves within Bone

“…• The proximal stump of mouse trigeminal ganglion neurons after transection of the inferior alveolar nerve [ 140 ]…”

“…[ 138 ] Sema3A secreted by bone lineage cells regulates neural activities through its receptor, neuropilin‐1. [ 139–143 ] Semaphorin 4D is strongly expressed by osteoclasts but not osteoblasts. [ 87,95,96,144 ] Sema4D derived from skeletal tissues can also modulate neural activities through receptors expressed on nerves.…”