Nerve Dependency in Scarless Fetal Wound Healing

The human fetus is capable of healing cutaneous wounds without scar up to the third trimester of development This process of tissue repair is more akin to newt limb regeneration than classic adult scar forming wound repair. Regeneration of the newt limb is dependent on neural input in its early stages. This study was an attempt to determine whether a similar dependence on neural input exists for mammalian fetal wounds to heal without scar. The left hind limb of six fetal lambs was denervated during the early second trimester of development (day 55; term = 145 days). Two weeks after denervation, the animals were again exposed to create bilateral incisional and 6-mm-diameter excisional wounds on their innervated right and denervated left lower extremities. Five days after creation of these defects, the wounds were examined for alterations in repair. Four fetal lambs survived, and three were suitable for evaluation. There were marked alterations in wound healing seen after denervation. Excisional wounds on the innervated side contracted and decreased their surface area by 14 percent. In contrast, the denervated wounds not only failed to contract, but increased in size by 60 percent. Changes in the incisional wounds were equally distinctive. Innervated incisional wounds healed completely without scar and had a wound breaking strength comparable to that of normal skin (Table I). In contrast, two of the three denervated incisional wounds dehisced and failed to heal, even in the regions where the skin was approximated by suture. The third denervated incisional wound did heal but with a significant amount of scar. Electron microscopy confirmed this finding by clearly demonstrating thickened and irregular collagen deposition in the extracellular matrix of all the denervated incisional specimens. In summary, like the regenerating newt limb, scarless fetal skin wound repair requires neural stimulation for tissue regeneration to occur. Therefore, in the mammal, the primary regulator for this unique type of tissue repair may have a central neural, rather than a local, tissue origin.