PANCREATIC GASTRIN STIMULATES ISLET DIFFERENTIATION OF TRANSFORMING GROWTH-FACTOR ALPHA-INDUCED DUCTULAR PRECURSOR CELLS
PANCREATIC GASTRIN STIMULATES ISLET DIFFERENTIATION OF TRANSFORMING GROWTH-FACTOR ALPHA-INDUCED DUCTULAR PRECURSOR CELLS
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DOI：
10.1172/jci116708
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发表时间：
1993-09-01
影响因子：
15.9
通讯作者：
BRAND, SJ
中科院分区：
文献类型：
--
作者：
WANG, TC;BONNERWEIR, S;BRAND, SJ
胃泌素在胎儿胰岛发育的关键期短暂表达，由胎儿胰管中的原分化胰岛前体发育而来。为了研究胃泌素作为胰岛细胞生长因子的可能作用，研究了在胰腺中过表达胃泌素和转化生长因子α的转基因小鼠出生后的胰岛生长。过表达转化生长因子α基因会导致含有大量胰岛素表达细胞的化生小管，这些细胞类似于胎儿胰腺的原始分化前体细胞。但转基因小鼠的胰岛质量未见增加。胰岛素启动子转录的胰岛素/胃泌素嵌合转基因的胰腺胃泌素的过度表达显著减少了TGFα刺激的胰管质量的增加。此外，胰腺胃泌素和转化生长因子α的共同表达显著增加了表达这两种转基因的小鼠的胰岛质量。这些发现表明，转化生长因子α和胃泌素可以协同作用来刺激胰岛生长，尽管这两种多肽本身都不够充分。胰岛生长可能是通过胃泌素促进转化生长因子α诱导的化生导管中胰岛素阳性细胞的分化来实现的。这项转基因研究表明，通过两种生长因子胃泌素和转化生长因子α的局部表达，可以在成年胰腺的胰管上皮细胞中重新激活胰岛新生。
Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet precursors in fetal pancreatic ducts. To examine the possible role of gastrin as an islet cell growth factor, postnatal islet growth was studied in transgenic mice which overexpress gastrin and TGFalpha in their pancreas. Overexpression of a TGFalpha transgene causes metaplastic ductules containing numerous insulin expressing cells that resemble protodifferentiated precursors of the fetal pancreas. However, islet mass of the TGFalpha transgenic mice was not increased. Pancreatic overexpression of gastrin from a chimeric insulin/gastrin transgene transcribed from the insulin promoter markedly decreased the TGFalpha-stimulated increase in pancreatic duct mass. Furthermore, pancreatic coexpression of both gastrin and TGFalpha significantly increased islet mass in mice expressing both transgenes. These findings indicate that TGFalpha and gastrin can act synergistically to stimulate islet growth, although neither peptide alone is sufficient. Islet growth may possibly be stimulated through gastrin promoting the differentiation of insulin-positive cells in the TGFalpha-induced metaplastic ducts. This transgenic study suggests that islet neogenesis can be reactivated in the ductular epithelium of the adult pancreas by local expression of two growth factors, gastrin and TGFalpha.