Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor.
Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor.
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DOI：
10.1084/jem.187.10.1565
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发表时间：
1998-05-18
影响因子：
15.3
通讯作者：
Longley, B J
中科院分区：
文献类型：
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作者：
Kunisada, T;Lu, S Z;Yoshida, H;Nishikawa, S;Nishikawa, S;Mizoguchi, M;Hayashi, S;Tyrrell, L;Williams, D A;Wang, X;Longley, B J
肥大细胞和黑素细胞的生长和分化需要干细胞因子（SCF），这是kit受体酪氨酸激酶的配体。SCF可以作为膜结合或可溶性分子存在。SCF-kit信号通路异常，局部可溶性SCF浓度升高，与人类疾病皮肤肥大细胞增多症的发病机制有关，但尚未显示其起因果作用。为了研究SCF引起肥大细胞增多症的潜力及其在表皮黑素细胞稳态中的作用，我们将SCF表达到表皮角质形成细胞的小鼠中，这些小鼠具有两种不同的转基因，由人类角蛋白14启动子控制。这些转基因含有的cdna要么产生SCF， SCF可以以膜结合和可溶性形式存在，要么产生SCF， SCF基本上保持膜结合。小鼠表皮角化细胞表达的膜结合/可溶性SCF再现了人类皮肤肥大细胞增多症的表型，伴有真皮肥大细胞浸润和表皮色素沉着，并导致附着物间表皮中黑色素细胞群的维持，这是在人类皮肤中发现黑色素细胞和黑色素的区域，但在小鼠皮肤中通常没有发现。单独表达膜结合的SCF可导致表皮黑色素细胞增多和黑色素生成，但本身不会引起肥大细胞增多。我们的结论是，首先，角化细胞过量产生可溶性SCF可以在小鼠中产生与人类肥大细胞增多症相匹配的表型，这表明该疾病的潜在原因。其次，我们得出结论，角化细胞表达的膜结合SCF导致小鼠出生后表皮黑色素细胞的维持。由于由此产生的动物的皮肤比正常小鼠更接近人类皮肤，因此他们的研究可能比正常小鼠的皮肤研究更与人类黑素细胞生物学有关。
The growth and differentiation of mast cells and melanocytes require stem cell factor (SCF), the ligand for the kit receptor tyrosine kinase. SCF may exist as a membrane-bound or soluble molecule. Abnormalities of the SCF-kit signaling pathway, with increased local concentrations of soluble SCF, have been implicated in the pathogenesis of the human disease cutaneous mastocytosis, but have not yet been shown to play a causal role. To investigate both the potential of SCF to cause mastocytosis and its role in epidermal melanocyte homeostasis, we targeted the expression of SCF to epidermal keratinocytes in mice with two different transgenes controlled by the human keratin 14 promoter. The transgenes contained cDNAs that either produced SCF, which can exist in both membrane-bound and soluble forms, or SCF, which remains essentially membrane bound. Murine epidermal keratinocyte expression of membrane-bound/ soluble SCF reproduced the phenotype of human cutaneous mastocytosis, with dermal mast cell infiltrates and epidermal hyperpigmentation, and caused the maintenance of a population of melanocytes in the interadnexal epidermis, an area where melanocytes and melanin are found in human skin but where they are not typically found in murine skin. Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and melanin production, but did not by itself cause mastocytosis. We conclude, first, that a phenotype matching that of human mastocytosis can be produced in mice by keratinocyte overproduction of soluble SCF, suggesting a potential cause of this disease. Second, we conclude that keratinocyte expression of membrane-bound SCF results in the postnatal maintenance of epidermal melanocytes in mice. Since the resulting animals have skin that more closely approximates human skin than do normal mice, their study may be more relevant to human melanocyte biology than the study of skin of normal mice.