Simeone Diane M, Zhang Lizhi, Treutelaar Mary K, Zhang Lanjing, Graziano Kathleen, Logsdon Craig D, Burant Charles F
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1305-16. doi: 10.1152/ajpendo.00561.2005. Epub 2006 May 30.
To investigate the role of transforming growth factor (TGF)-beta family signaling in the adult pancreas, a transgenic mouse (E-dnSmad4) was created that expresses a dominant-negative Smad4 protein driven by a fragment of the elastase promoter. Although E-dnSmad4 mice have normal growth, pancreas weight, and pancreatic exocrine and ductal histology, beginning at 4-6 wk of age, E-dnSmad4 mice show an age-dependent increase in the size of islets. In parallel, an expanded population of replicating cells expressing the E-dnSmad4 transgene is found in the stroma between the enlarged islets and pancreatic ducts. Despite the marked enlargement, E-dnSmad4 islets contain normal ratios and spatial organization of endocrine cell subtypes and have normal glucose homeostasis. Replication of cells derived from primary duct cultures of wild-type mice, but not E-dnSmad4 mice, was inhibited by the addition of TGF-beta family proteins, demonstrating a cell-autonomous effect of the transgene. These data show that, in the adult pancreas, TGF-beta family signaling plays a role in islet size by regulating the growth of a pluripotent progenitor cell residing in the periductal stroma of the pancreas.
为了研究转化生长因子（TGF）-β家族信号在成年胰腺中的作用，构建了一种转基因小鼠（E-dnSmad4），其表达由弹性蛋白酶启动子片段驱动的显性负性Smad4蛋白。尽管E-dnSmad4小鼠生长正常、胰腺重量正常、胰腺外分泌和导管组织学正常，但从4-6周龄开始，E-dnSmad4小鼠的胰岛大小呈现年龄依赖性增加。同时，在扩大的胰岛和胰腺导管之间的基质中发现了表达E-dnSmad4转基因的复制细胞群体有所扩大。尽管胰岛明显增大，但E-dnSmad4胰岛中内分泌细胞亚型的比例和空间组织正常，且葡萄糖稳态正常。添加TGF-β家族蛋白可抑制野生型小鼠而非E-dnSmad4小鼠原代导管培养细胞的复制，这表明该转基因具有细胞自主效应。这些数据表明，在成年胰腺中，TGF-β家族信号通过调节胰腺导管周围基质中多能祖细胞的生长，在胰岛大小方面发挥作用。
