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.

中文翻译：

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靶向腺泡 KLF4 的优化 rAAV8 通过富含外泌体的 let-7 抑制胰腺星状细胞活化，改善慢性胰腺炎的纤维化


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，并伴有胰腺实质的破坏，导致腺泡细胞（AC）的损失。很少有研究探讨受损 AC (DAC) 导致 PSC 激活和胰腺纤维化的机制。目前，尚无有效的药物可以治愈CP或限制胰腺纤维化的进展。在这项研究中，与完整腺泡细胞 (IAC) 共培养抑制 PSC 激活，而与 DAC 共培养则起到相反的作用。 Krüppel 样因子 4 (KLF4) 在 DAC 中显着上调，并被确定为将 AC 从 PSC 抑制剂转变为 PSC 激活剂的关键分子。我们发现 IAC 的外泌体有助于 IAC-CS 对 PSC 的抗激活功能。 MiRNome 分析显示，let-7 家族在 IAC 衍生的外泌体 (>30% miRNome) 中显着富集，这部分介导了 IAC 对 PSC 的抑制作用。此外，还观察到let-7在外泌体中的富集受到KLF4表达水平的影响。机制研究表明，AC 中的 KLF4 上调 Lin28A，从而降低 AC 衍生的外泌体中的 let-7 水平，从而促进 PSC 激活。我们利用一种专门针对 AC 中 KLF4 的腺相关病毒 (shKLF4-pAAV) 来抑制 CP 中 PSC 的激活，从而减少胰腺纤维化。 IAC 衍生的外泌体具有作为对抗通过 let-7 激活 PSC 的有效武器的潜力，而 DAC 中激活的 KLF4/Lin28A 信号传导削弱了此类功能。 ShKLF4-pAAV 有望成为一种新型的 CP 治疗方法。