Lineage Tracing Evidence for Transdifferentiation of Acinar to Duct Cells and Plasticity of Human Pancreas
Lineage Tracing Evidence for Transdifferentiation of Acinar to Duct Cells and Plasticity of Human Pancreas
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DOI：
10.1053/j.gastro.2011.04.050
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发表时间：
2011-08-01
期刊：
影响因子：
29.4
通讯作者：
Bouwens, Luc
中科院分区：
文献类型：
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作者：
Houbracken, Isabelle;de Waele, Evelien;Bouwens, Luc
背景与目的：动物实验表明胰腺外分泌腺泡细胞具有表型可塑性。在啮齿动物中，腺泡细胞可以分化为导管前体细胞，这些导管前体细胞可以转化为胰腺导管腺癌或产生胰岛素的内分泌细胞。然而，对人腺泡细胞的可塑性知之甚少。我们开发了非遗传和遗传谱系追踪方法来研究人腺泡细胞在培养中的命运。方法：取器官供者外分泌组织，分离培养。检测细胞增殖和存活情况，免疫细胞化学分析细胞表型。基于腺泡细胞选择性结合和摄取标记的凝集素(Ulex Uropaeus Agherinin 1)，发展了非遗传示踪方法。基于腺病毒导入由淀粉酶启动子控制的Cre-lox报告系统，开发了遗传示踪方法。结果：两种示踪方法均显示人腺泡细胞可以转分化为表达特异性导管标志物的细胞，如细胞角蛋白19、肝细胞核因子1β、SOX9、CD133、碳酸氢酶II和囊性纤维化跨膜电导调节因子。在培养的1周内，所有存活的腺泡细胞都获得了导管表型。这种转分化通过抑制丝裂原活化蛋白激酶信号而减少。结论：人腺泡细胞具有与啮齿动物细胞相似的可塑性。这些结果可能被用来开发糖尿病或胰腺癌患者的治疗策略。
BACKGROUND & AIMS: Animal studies have indicated that pancreatic exocrine acinar cells have phenotypic plasticity. In rodents, acinar cells can differentiate into ductal precursors that can be converted to pancreatic ductal adenocarcinoma or insulin-producing endocrine cells. However, little is known about human acinar cell plasticity. We developed nongenetic and genetic lineage tracing methods to study the fate of human acinar cells in culture. METHODS: Human exocrine tissue was obtained from organ donors, dissociated, and cultured. Cell proliferation and survival were measured, and cell phenotypes were analyzed by immunocytochemistry. Nongenetic tracing methods were developed based on selective binding and uptake by acinar cells of a labeled lectin (Ulex europaeus agglutinin 1). Genetic tracing methods were developed based on adenoviral introduction of a Cre-lox reporter system, controlled by the amylase promoter. RESULTS: Both tracing methods showed that human acinar cells can transdifferentiate into cells that express specific ductal markers, such as cytokeratin 19, hepatocyte nuclear factor 1 beta, SOX9, CD133, carbonic anhydrase II, and cystic fibrosis transmembrane conductance regulator. Within 1 week of culture, all surviving acinar cells had acquired a ductal phenotype. This transdifferentiation was decreased by inhibiting mitogen-activated protein kinase signaling. CONCLUSIONS: Human acinar cells have plasticity similar to that described in rodent cells. These results might be used to develop therapeutic strategies for patients with diabetes or pancreatic cancer.