The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited fibroblasts

Neurofibromatosis type 1 patients develop peripheral nerve tumors (neurofib romas) composed mainly of Schwann cells and fibroblasts, in an abundant col lagen matrix produced by fibroblasts. Trauma has been proposed to trigger n eurofibroma formation. To test if loss of the neurofibromatosis type 1 gene (Nf1) compromises fibroblast function in vivo following trauma, skin wound ing was performed in Nf1 knockout mice. The pattern and amount of collagen- rich granulation bed tissue, manufactured by fibroblasts, was grossly abnor mal in 60% of Nf1+/- wounds. Nf1 mutant fibroblasts showed cell autonomous abnormalities in collagen deposition in vitro that were not mimicked by Ras activation in fibroblasts, even though some Nf1 effects are mediated throu gh Ras, Nf1+/- skin wound fibroblasts also proliferated past the normal wou nd maturation phase; this in vivo effect was potentiated by muscle injury. In vitro, Nf1+/- fibroblasts showed higher proliferation in 10% serum than Nf1+/+ fibroblasts. Macrophage-conditioned media or epidermal growth factor potentiated Nf1+/- fibroblast proliferation in vitro, demonstrating abnorm al response of mutant fibroblasts to wound cytokines. Thus Nf1 is a key reg ulator of fibroblast responses to injury, and Nf1 mutation in mouse fibrobl asts causes abnormalities characteristic of human neurofibromas.