Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function.
Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function.
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DOI：
10.1371/journal.pgen.1009069
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发表时间：
2020-10
期刊：
影响因子：
4.5
通讯作者：
Constância M
中科院分区：
文献类型：
--
作者：
Hammerle CM;Sandovici I;Brierley GV;Smith NM;Zimmer WE;Zvetkova I;Prosser HM;Sekita Y;Lam BYH;Ma M;Cooper WN;Vidal-Puig A;Ozanne SE;Medina-Gómez G;Constância M
决定成人胰腺大小的遗传机制知之甚少。印迹基因以亲本特异性方式表达，已知在发育、生长和代谢中具有重要作用。然而，我们对它们在控制胰腺生长和功能中的作用的了解仍然有限。在这里，我们发现，许多印迹基因在胰腺间充质来源的细胞中高度表达，并探讨了父系表达的胰岛素样生长因子2（Igf2）基因在间充质和上皮胰腺谱系中的作用，使用新开发的条件Igf2小鼠模型。间充质特异性Igf2缺失导致腺泡和β细胞发育不全、出生后全身生长受限和妊娠期间母体葡萄糖耐受不良，这表明间充质是用于旁分泌信号传导的IGF2的发育储库。间充质IGF2的独特作用通过在发育中的胰腺上皮中Igf2缺失后不存在任何可辨别的生长或功能表型来证明。此外，通过条件性Igf2印迹缺失或Igf2r缺失，间充质中特异性IGF2水平增加，导致胰腺腺泡过度生长。此外，原代腺泡细胞离体暴露于外源性IGF2激活AKT，一个关键的信号传导节点，并增加其数量和淀粉酶的产生。基于这些发现，我们提出间充质Igf2，也许还有其他印记基因，是成年胰腺大小和功能的关键发育调节因子。胰腺由两个主要组成部分组成：外分泌胰腺（产生消化酶，分解食物，使其易于被肠道吸收）和内分泌胰腺（产生胰岛素和其他控制血糖水平的激素）。此外，胰腺含有支持外分泌和内分泌成分功能的基质细胞（间充质来源的细胞）。我们对胰腺如何达到正常大小知之甚少。在这项研究中，使用小鼠遗传工程，我们探索了一种名为Igf2的类似胰岛素的基因所起的作用，该基因在结构上与胰岛素相似，并且仅在从父亲遗传的染色体上活跃。我们发现，在胰腺内，Igf2主要活跃在间充质来源的细胞中。当Igf2在这些细胞中丢失时，整个胰腺变得更小，产生消化酶和维持正常血糖水平的能力降低。间充质来源的细胞中IGF2水平的增加导致胰腺变大，而当Igf2在外分泌和内分泌胰腺中丢失时，没有观察到任何影响。我们的研究结果表明，间充质来源的细胞中的Igf2活性是控制胰腺大小和功能的关键。
The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function. The pancreas is formed of two main components: the exocrine pancreas (producing digestive enzymes that break down food so it can be easily absorbed by the intestine) and the endocrine pancreas (producing insulin and other hormones that control blood sugar levels). Additionally, the pancreas contains stromal cells (mesenchyme-derived cells) that support the function of the exocrine and endocrine components. We know little about how the pancreas reaches its normal size. In this study, using mouse genetic engeneering, we explored the roles played by a hormone-like gene called Igf2, that is similar in structure to insulin, and is active only on the chromosome inherited from the father. We found that within the pancreas, Igf2 is mostly active in the mesenchyme-derived cells. When Igf2 is lost specifically within these cells, the entire pancreas becomes smaller, with reduced capacity to produce digestive enzymes and to maintain normal blood sugar levels during pregnancy. Increased IGF2 levels in the mesenchyme-derived cells leads to a larger pancreas, while no effects are observed when Igf2 is lost in the exocrine and endocrine pancreas. Our results demonstrate that Igf2 activity in mesenchyme-derived cells is key for the control of pancreas size and function.
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