Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice
Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice
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DOI：
10.1002/1873-3468.13504
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发表时间：
2019-06-30
期刊：
影响因子：
3.5
通讯作者：
Kawaguchi, Yoshiya
中科院分区：
文献类型：
--
作者：
Horiguchi, Masashi;Yoshida, Masahiro;Kawaguchi, Yoshiya
在这项研究中，我们利用他莫昔芬诱导的弹性蛋白酶-Cre介导的胰腺和十二指肠同源盒1（Pdx1）（胚胎胰腺发生过程中不可或缺的基因）的失活来研究Pdx1在成人胰腺外分泌组织中的作用。我们发现大约 50% 的腺泡细胞团中 Pdx1 缺失没有表现出任何宏观表型。谱系追踪实验显示，Pdx1缺失的细胞百分比最初没有变化，而是逐渐下降，而Pdx1保留的细胞增殖增加。电镜分析显示出现圆形线粒体，嵴较少，内质网管腔扩张，自噬体数量增加，但没有细胞凋亡。相反，Pdx1耗尽的腺泡细胞变得衰老。这些发现表明，Pdx1 失活引起的细胞内应激会触发衰老相关的分泌表型，以维持该模型中的器官稳态。
In this study, we used tamoxifen-inducible Elastase-Cre-mediated inactivation of pancreatic and duodenal homeobox1 (Pdx1), an indispensable gene during embryonic pancreatogenesis, to investigate the role of Pdx1 in adult pancreatic exocrine tissue. We found that Pdx1 depletion in approximately 50% of acinar cell mass did not show any macroscopic phenotype. Lineage tracing experiments revealed that the percentage of Pdx1-depleted cells did not change initially but gradually decreased, while the proliferation of Pdx1-preserved cells increased. Electron microscopic analysis showed the emergence of round-shaped mitochondria with less cristae, dilated ER lumen and increased number of autophagosomes but no apoptosis. Instead, Pdx1-depleted acinar cells became senescent. These findings indicate that intracellular stress caused by Pdx1 inactivation triggers the senescence-associated secretory phenotype to maintain organ homeostasis in this model.