Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells
Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells
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DOI：
10.1073/pnas.0507567102
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发表时间：
2005-10-18
影响因子：
11.1
通讯作者：
Seino, S
中科院分区：
文献类型：
--
作者：
Minami, K;Okuno, M;Seino, S
虽然有几项研究表明，胰岛素分泌细胞可以在体外产生的细胞居住在成人外分泌胰腺，既没有这些细胞的起源，也没有获得其精确的胰岛素分泌特性。我们在这里表明，在EGF和烟酰胺存在下，通过悬浮培养可以从成年小鼠胰腺外分泌细胞中获得胰岛素分泌细胞。胰岛素阳性细胞的频率在初始制备中仅为0.01%，在培养条件下增加至约5%。通过基于Cre/IoxP的直接细胞谱系追踪系统的分析表明，这些新制造的细胞来源于表达淀粉酶/弹性蛋白酶的胰腺腺泡细胞。葡萄糖、磺脲类和卡巴胆碱可刺激胰岛素分泌，胰高血糖素样肽-1也可增强胰岛素分泌。这些细胞中含有含胰岛素的分泌颗粒。此外，我们发现胰腺腺泡本身的酶促解离导致EGF信号转导的激活，并且EGF受体激酶的抑制阻断转分化。这些数据表明，胰腺腺泡细胞可以转分化成具有与天然胰腺β细胞相似的分泌特性的胰岛素分泌细胞，并且在这种转分化中需要EGF信号传导的激活。
Although several studies have suggested that insulin-secreting cells can be generated in vitro from cells residing in adult exocrine pancreas, neither the origin of these cells nor their precise insulin secretory properties was obtained. We show here that insulin-secreting cells can be derived from adult mouse pancreatic exocrine cells by suspension culture in the presence of EGF and nicotin-amide. The frequency of insulin-positive cells was only 0.01% in the initial preparation and increased to approximate to 5% in the culture conditions. Analysis by the Cre/IoxP-based direct cell lineage tracing system indicates that these newly made cells originate from amylase/elastase-expressing pancreatic acinar cells. Insulin secretion is stimulated by glucose, sulfonylurea, and carbachol, and potentiation by glucagon-like peptide-1 also occurs. Insulin-containing secretory granules are present in these cells. In addition, we found that the enzymatic dissociation of pancreatic acini itself leads to activation of EGF signaling, and that inhibition of EGF receptor kinase blocks the transdifferentiation. These data demonstrate that pancreatic acinar cells can transdifferentiate into insulin-secreting cells with secretory properties similar to those of native pancreatic beta cells, and that activation of EGF signaling is required in such transdifferentiation.