Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232-0443, USA.
Development. 2010 Jul;137(14):2289-96. doi: 10.1242/dev.048421. Epub 2010 Jun 9.
Studies in both humans and rodents have found that insulin(+) cells appear within or near ducts of the adult pancreas, particularly following damage or disease, suggesting that these insulin(+) cells arise de novo from ductal epithelium. We have found that insulin(+) cells are continuous with duct cells in the epithelium that makes up the hyperplastic ducts of both chronic pancreatitis and pancreatic cancer in humans. Therefore, we tested the hypothesis that both hyperplastic ductal cells and their associated insulin(+) cells arise from the same cell of origin. Using a mouse model that develops insulin(+) cell-containing hyperplastic ducts in response to the growth factor TGFalpha, we performed genetic lineage tracing experiments to determine which cells gave rise to both hyperplastic ductal cells and duct-associated insulin(+) cells. We found that hyperplastic ductal cells arose largely from acinar cells that changed their cell fate, or transdifferentiated, into ductal cells. However, insulin(+) cells adjacent to acinar-derived ductal cells arose from pre-existing insulin(+) cells, suggesting that islet endocrine cells can intercalate into hyperplastic ducts as they develop. We conclude that apparent pancreatic plasticity can result both from the ability of acinar cells to change fate and of endocrine cells to reorganize in association with duct structures.
在人类和啮齿动物中的研究发现，胰岛素(+)细胞出现在成年胰腺的导管内或附近，特别是在损伤或疾病后，这表明这些胰岛素(+)细胞是从头从导管上皮产生的。我们发现，在由构成人类慢性胰腺炎和胰腺癌的增生导管的上皮组成的细胞中，胰岛素(+)细胞与导管细胞连续存在。因此，我们检验了以下假说，即增生的导管细胞及其相关的胰岛素(+)细胞都起源于相同的祖细胞。使用一种在生长因子 TGFalpha 作用下发展为含有胰岛素(+)细胞的增生导管的小鼠模型，我们进行了遗传谱系追踪实验，以确定哪些细胞产生了增生的导管细胞和导管相关的胰岛素(+)细胞。我们发现，增生的导管细胞主要来源于腺泡细胞，这些腺泡细胞改变了它们的细胞命运，即转分化为导管细胞。然而，与腺泡衍生的导管细胞相邻的胰岛素(+)细胞来自于预先存在的胰岛素(+)细胞，这表明胰岛内分泌细胞可以在增生导管发育过程中插入其中。我们的结论是，胰腺的明显可塑性既可以归因于腺泡细胞改变命运的能力，也可以归因于内分泌细胞与导管结构重新组织的能力。
