Silencing Mist1 Gene Expression Is Essential for Recovery from Acute Pancreatitis.
Silencing Mist1 Gene Expression Is Essential for Recovery from Acute Pancreatitis.
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DOI：
10.1371/journal.pone.0145724
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Konieczny SF
中科院分区：
文献类型：
--
作者：
Karki A;Humphrey SE;Steele RE;Hess DA;Taparowsky EJ;Konieczny SF
胰腺外分泌腺泡细胞的任务是合成、包装和分泌大量的消化酶，以维持机体适当的代谢平衡。由于高水平水解酶的合成具有潜在的危险，胰腺容易发生急性胰腺炎(AP)，这是一种以腺泡细胞为靶点的疾病，导致腺泡导管化生(ADM)、炎症和纤维化-这些事件可以过渡到胰腺导管腺癌的早期阶段。尽管关于胰腺炎相关的广泛表型有丰富的信息，但对AP易感的特定转录调控网络以及这些网络在腺泡细胞和外分泌胰腺反应中所起的作用知之甚少。在这项研究中，我们研究了腺泡特异性成熟转录因子MIST1对AP损伤和器官恢复的重要性。对野生型和Mist1条件缺失小鼠的分析表明，随着腺泡细胞在AP发作期间经历ADM改变，Mist1基因转录和蛋白质积累显著减少。为了测试MIST1功能的丧失是否是器官受损状态的主要原因，研究人员利用携带CRE诱导的Mist1转基因(IMist1)的小鼠来确定持续的MIST1活动是否可以减轻AP的损伤反应。出乎意料的是，在AP期间，结构性的iMist1表达导致器官损伤急剧增加，随后腺泡细胞死亡。我们的结论是，Mist1表达的短暂沉默对于腺泡细胞在AP发作中存活至关重要，这为细胞提供了一个抑制其分泌功能和再生受损细胞的机会。MIST1在这些事件中的重要性表明，调节关键的胰腺转录网络可以缓解被诊断为胰腺炎和胰腺癌的患者的临床症状。
Acinar cells of the exocrine pancreas are tasked with synthesizing, packaging and secreting vast quantities of pro-digestive enzymes to maintain proper metabolic homeostasis for the organism. Because the synthesis of high levels of hydrolases is potentially dangerous, the pancreas is prone to acute pancreatitis (AP), a disease that targets acinar cells, leading to acinar-ductal metaplasia (ADM), inflammation and fibrosis—events that can transition into the earliest stages of pancreatic ductal adenocarcinoma. Despite a wealth of information concerning the broad phenotype associated with pancreatitis, little is understood regarding specific transcriptional regulatory networks that are susceptible to AP and the role these networks play in acinar cell and exocrine pancreas responses. In this study, we examined the importance of the acinar-specific maturation transcription factor MIST1 to AP damage and organ recovery. Analysis of wild-type and Mist1 conditional null mice revealed that Mist1 gene transcription and protein accumulation were dramatically reduced as acinar cells underwent ADM alterations during AP episodes. To test if loss of MIST1 function was primarily responsible for the damaged status of the organ, mice harboring a Cre-inducible Mist1 transgene (iMist1) were utilized to determine if sustained MIST1 activity could alleviate AP damage responses. Unexpectedly, constitutive iMist1 expression during AP led to a dramatic increase in organ damage followed by acinar cell death. We conclude that the transient silencing of Mist1 expression is critical for acinar cells to survive an AP episode, providing cells an opportunity to suppress their secretory function and regenerate damaged cells. The importance of MIST1 to these events suggests that modulating key pancreas transcription networks could ease clinical symptoms in patients diagnosed with pancreatitis and pancreatic cancer.