Abstract：
Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSCs), accompanied by the destruction of pancreatic parenchyma, leading to the loss of acinar cells (ACs). Few research studies have explored the mechanism by which damaged ACs (DACs) contribute to PSCs activation and pancreatic fibrosis. Currently, there are no effective drugs for curing CP or limiting the progression of pancreatic fibrosis. In this research, co-culture with intact acinar cells (IACs) suppressed PSC activation, while co-culture with DACs did the opposite. Krüppel-like factor 4 (KLF4) was significantly upregulated in DACs and was established as the key molecule that switches ACs from PSCs-suppressor to PSCs-activator. We revealed the exosomes of IACs contributed to the anti-activated function of IACs-CS on PSCs. MiRNome profiling showed that let-7 family is significantly enriched in IAC-derived exosomes (>30% miRNome), which partially mediates IACs\' suppressive impacts on PSCs. Furthermore, it has been observed that the enrichment of let-7 in exosomes was influenced by the expression level of KLF4. Mechanistic studies demonstrated that KLF4 in ACs upregulated Lin28A, thereby decreasing let-7 levels in AC-derived exosomes, and thus promoting PSCs activation. We utilized an adeno-associated virus specifically targeting KLF4 in ACs (shKLF4-pAAV) to suppress PSCs activation in CP, resulting in reduced pancreatic fibrosis. IAC-derived exosomes hold potential as potent weapons against PSCs activation via let-7s, while activated KLF4/Lin28A signaling in DACs diminished such functions. ShKLF4-pAAV holds promise as a novel therapeutic approach for CP.
摘要：
慢性胰腺炎（CP）的特点是进行性纤维化和胰腺星状细胞（PSC）的激活，伴随着胰腺实质的破坏，导致腺泡细胞（AC）的损失。很少有研究探讨受损AC（DACs）促进PSC活化和胰腺纤维化的机制。目前,目前尚无治疗CP或限制胰腺纤维化进展的有效药物。在这项研究中,与完整腺泡细胞（IACs）共培养抑制PSC活化，而与DAC的共同文化则相反。Krüppel样因子4（KLF4）在DAC中被显着上调，并被确立为将AC从PSC抑制剂转换为PSC激活剂的关键分子。我们揭示了IACs的外泌体有助于IACs-CS对PSC的抗激活功能。MiRNome谱分析显示let-7家族在IACs衍生的外泌体中显著富集(>30%miRNome),部分介导IAC对PSC的抑制性影响。此外，已经观察到,外来体中let-7的富集受KLF4表达水平的影响。机理研究表明，KLF4在AC中上调Lin28A，从而降低AC衍生的外泌体中的let-7s水平，从而促进PSC活化。我们利用特异性靶向AC中的KLF4的腺相关病毒（shKLF4-pAAV）来抑制CP中的PSC活化，导致胰腺纤维化减少。IACs衍生的外泌体具有作为通过let-7s抵抗PSC激活的有效武器的潜力，而在DAC中激活KLF4/Lin28A信号则削弱了此类功能。ShKLF4-pAAV有望成为CP的新型治疗方法。
