The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited fibroblasts
The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited fibroblasts
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DOI：
10.1046/j.1523-1747.1999.00609.x
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发表时间：
1999-06-01
影响因子：
6.5
通讯作者：
Ratner, N
中科院分区：
文献类型：
--
作者：
Atit, RP;Crowe, MJ;Ratner, N
1型神经纤维瘤病患者发生周围神经肿瘤(神经纤维瘤)，主要由雪旺细胞和成纤维细胞组成，由成纤维细胞产生丰富的胶原基质。创伤被认为是神经纤维瘤形成的诱因。为了测试神经纤维瘤病1型基因(NF1)的缺失是否会损害创伤后体内的成纤维细胞功能，对NF1基因敲除的小鼠进行了皮肤损伤。在60%的NF1+/-创面中，成纤维细胞产生的富胶原肉芽组织的形态和数量明显异常。NF1突变的成纤维细胞在体外表现出不能被RAS激活的细胞自主的胶原沉积异常，即使一些NF1的作用是通过RAS介导的，NF1+/-皮肤创伤成纤维细胞也在正常伤口成熟期后增殖；这种在体内的作用因肌肉损伤而增强。在体外，NF1+/-成纤维细胞在10%的血清中表现出比NF1+/+成纤维细胞更高的增殖。巨噬细胞条件培养液或表皮生长因子在体外促进NF1+/-成纤维细胞的增殖，显示突变的成纤维细胞对创伤细胞因子的异常反应。因此，NF1是成纤维细胞对损伤反应的关键调节因子，而小鼠成纤维细胞中的NF1突变导致了人类神经纤维瘤特有的异常。
Neurofibromatosis type 1 patients develop peripheral nerve tumors (neurofibromas) composed mainly of Schwann cells and fibroblasts, in an abundant collagen matrix produced by fibroblasts. Trauma has been proposed to trigger neurofibroma formation. To test if loss of the neurofibromatosis type 1 gene (Nf1) compromises fibroblast function in vivo following trauma, skin wounding was performed in Nf1 knockout mice. The pattern and amount of collagen-rich granulation bed tissue, manufactured by fibroblasts, was grossly abnormal 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 through Ras, Nf1+/- skin wound fibroblasts also proliferated past the normal wound 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 abnormal response of mutant fibroblasts to wound cytokines. Thus Nf1 is a key regulator of fibroblast responses to injury, and Nf1 mutation in mouse fibroblasts causes abnormalities characteristic of human neurofibromas.