Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia
Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia
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DOI：
10.1053/gast.2003.50150
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发表时间：
2003-04-01
期刊：
影响因子：
29.4
通讯作者：
Leach, SD
中科院分区：
文献类型：
--
作者：
Means, AL;Ray, KC;Leach, SD
背景和目标：肝素结合表皮生长因子样生长因子（HB-EGF）在正常胰岛和胰腺癌中均有表达，但其在胰腺生理学和疾病中的作用尚不清楚。本报告研究了小鼠胰腺中HB-EGF过表达的影响。研究方法：使用组织特异性启动子建立转基因小鼠，以在胰腺β细胞中表达HB-EGF互补DNA，有效地将HB-EGF蛋白质提高到内源性水平的3倍。结果：胰岛细胞过度表达HB-EGF可引起胰腺内分泌和外分泌功能的改变。最初，来自转基因小鼠的胰岛未能在胰岛内适当地分离α、β、δ和PP细胞，并且与导管和腺泡的分离受损。在转基因胰岛内检测到基质增加，随着年龄的增长而扩大，导致内分泌和外分泌室纤维化。除了这些结构异常外，转基因小鼠的亚群还出现了严重的高血糖和/或化生性导管上皮细胞增殖。这两种情况都与严重的间质扩张有关，表明胰岛/间质相互作用在HB-EGF引发的胰腺疾病发病中起作用。支持这一结论，原代小鼠成纤维细胞粘附转基因胰岛时，2个组织在体外共培养，但不与非转基因胰岛相互作用。结论：胰岛中HB-EGF蛋白的升高导致胰岛细胞之间以及胰岛、间质组织和导管上皮之间的相互作用改变。许多观察到的表型似乎涉及改变细胞粘附。这些数据支持胰岛因子在内分泌和外分泌疾病的发展中的作用。
Background & Aims: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is expressed in both normal pancreatic islets and in pancreatic cancers, but its role in pancreatic physiology and disease is not known. This report examines the effects of HB-EGF overexpression in mouse pancreas. Methods: Transgenic mice were established using a tissue-specific promoter to express an HB-EGF complementary DNA in pancreatic beta cells, effectively elevating HB-EGF protein 3-fold over endogenous levels. Results: Mice overexpressing HB-EGF in pancreatic islets showed both endocrine and exocrine pancreatic defects. Initially, islets from transgenic mice failed to segregate alpha, beta, delta, and PP cells appropriately within islets, and had impaired separation from ducts and acini. Increased stroma was detected within transgenic islets, expanding with age to cause fibrosis of both endocrine and exocrine compartments. In addition to these structural abnormalities, subsets of transgenic mice developed profound hyperglycemia and/or proliferation of metaplastic ductal epithelium. Both conditions were associated with severe stromal expansion, suggesting a role for islet/stromal interaction in the onset of the pancreatic disease initiated by HB-EGF. Supporting this conclusion, primary mouse fibroblasts adhered to transgenic islets when the 2 tissues were cocultured in vitro, but did not interact with nontransgenic islets. Conclusions: An elevation in HB-EGF protein in pancreatic islets led to altered interactions among islet cells and among islets, stromal tissues, and ductal epithelium. Many of the observed phenotypes appeared to involve altered cell adhesion. These data support a role for islet factors in the development of both endocrine and exocrine disease.