Silencing Mist1 Gene Expression Is Essential for Recovery from Acute Pancreatitis

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.外分泌胰腺的腺泡细胞负责合成、包装并分泌大量消化酶原，以维持机体正常的代谢稳态。由于高水平水解酶的合成存在潜在风险，胰腺极易罹患急性胰腺炎（acute pancreatitis，AP）——该疾病以腺泡细胞为靶标，可引发腺泡-导管化生（acinar-ductal metaplasia，ADM）、炎症及纤维化，上述病变进程可进展至胰腺导管腺癌的早期阶段。尽管目前已有大量关于胰腺炎相关广谱表型的研究数据，但对于急性胰腺炎易感性的特异性转录调控网络，以及这些网络在腺泡细胞及外分泌胰腺应答过程中发挥的作用，我们仍知之甚少。本研究聚焦腺泡细胞特异性成熟转录因子MIST1在急性胰腺炎损伤及器官修复中的作用。通过对野生型及Mist1条件性敲除小鼠的分析，我们发现，在急性胰腺炎发作期间，腺泡细胞发生腺泡-导管化生改变时，Mist1基因的转录水平及其蛋白积累量均显著降低。为验证MIST1功能缺失是否是导致器官损伤的核心原因，我们利用携带Cre诱导型Mist1转基因（iMist1）的小鼠，探究持续维持MIST1活性是否能够缓解急性胰腺炎的损伤应答。出乎意料的是，在急性胰腺炎进程中组成型表达iMist1，反而会导致器官损伤显著加剧，并伴随腺泡细胞死亡。我们由此得出结论：Mist1表达的瞬时沉默对于腺泡细胞在急性胰腺炎发作期间存活至关重要，这一过程为细胞抑制其分泌功能并修复受损组织提供了契机。MIST1在上述进程中的关键作用提示，调控胰腺核心转录网络或可改善胰腺炎及胰腺癌患者的临床症状。