Exocrine tissue-driven TFF2 prevents apoptotic cell death of endocrine lineage during pancreas organogenesis
Exocrine tissue-driven TFF2 prevents apoptotic cell death of endocrine lineage during pancreas organogenesis
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DOI：
10.1038/s41598-018-38062-9
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发表时间：
2019-02-07
影响因子：
4.6
通讯作者：
Kawaguchi, Yoshiya
中科院分区：
文献类型：
--
作者：
Hirata, Koji;Kodama, Sota;Kawaguchi, Yoshiya
在胚胎发生期间，外分泌和内分泌胰腺组织在小鼠分支导管结构内的不同区域形成。我们以前报道过，弹性蛋白酶Cre对Pdx 1的外分泌特异性失活不仅导致发育不良的外分泌形成，而且导致大量的内分泌缺陷，从而导致糖尿病表型，这表明存在调节适当内分泌发育的外分泌驱动因子。在这项研究中，我们确定了三叶因子2（TFF 2）作为一种外分泌基因表达从胚胎第16.5天到成年正常小鼠，但显着减少在我们的Pdx 1突变体。使用胚胎胰腺组织的体外外植体培养，我们证明，TFF 2防止胰岛素产生细胞的凋亡，但拮抗CXCR 4，一个已知的TFF 2受体，抑制这种抗凋亡作用的突变体。此外，正常胰腺组织中的拮抗剂加速了胰岛素产生细胞的凋亡，表明TFF 2/CXCR 4轴维持胚胎胰岛素产生细胞的正常发育。TFF 2还抑制突变胰腺中Nkx6.1+内分泌前体细胞的凋亡，但这种作用不受CXCR 4拮抗剂的干扰，表明TFF 2存在未知受体。这些发现表明TFF 2是一种新的外分泌因子，通过不同的受体支持内分泌细胞在器官发生的多个阶段中的存活。
During embryogenesis, exocrine and endocrine pancreatic tissues are formed in distinct regions within the branched ductal structure in mice. We previously reported that exocrine-specific inactivation of Pdx1 by Elastase-Cre caused not only hypoplastic exocrine formation but also substantial endocrine defects resulting in diabetic phenotype, indicating the existence of an exocrine-driven factor(s) that regulates proper endocrine development. In this study, we identified Trefoil Factor 2 (TFF2) as an exocrine gene expressed from embryonic day 16.5 to adulthood in normal mice but significantly less in our Pdx1 mutants. Using in vitro explant culture of embryonic pancreatic tissue, we demonstrated that TFF2 prevented the apoptosis of insulin-producing cells but that antagonizing CXCR4, a known TFF2 receptor, suppressed this anti-apoptotic effect in the mutants. Furthermore, the antagonist in normal pancreatic tissue accelerated the apoptosis of insulin-producing cells, indicating that the TFF2/CXCR4 axis maintains embryonic insulin-producing cells in normal development. TFF2 also suppressed the apoptosis of Nkx6.1+ endocrine precursors in mutant pancreata, but this effect was unperturbed by the CXCR4 antagonist, suggesting the existence of an unknown receptor for TFF2. These findings suggest TFF2 is a novel exocrine factor that supports the survival of endocrine cells in the multiple stages of organogenesis through distinct receptors.