胰腺基质水凝胶诱导巨噬细胞M2型极化减轻重症胰腺炎损伤的机制研究

Severe pancreatitis (SAP) is a serious threat to human health. Macrophage activation plays an important role during the progression of SAP. Recently, decellularized biomaterial has caused great attention in the field of regenerative medicine. It has been reported that it can direct cell behavior and promote tissue repair. However, its mechanism remains unclear; especially, the roles in pancreatic injury remains unclear. Our preliminary study found that pancreatic extracellular matrix (ECM) hydrogels could reduce SAP damage, and a large number of M2 macrophages were noted in the damaged region. We also found that miRNA play an important role during the progression of SAP. Based on above, we will prepare pancreatic ECM hydrogels and evaluate its physical, chemical properties and biocompatibility. ECM hydrogels will be injected into rat with SAP to study its effect on the mobilization of endogenous acinar cell and macrophage polarization. Furthermore, by in vivo intervention in macrophages and in vitro local inflammation model, we will clarify the role of macrophage polarization in hydrogel for repairing SAP. Finally, through miRNA chip, Real-time PCR and intervention, we will explore the role of specific miRNA in the regulation of macrophage polarization, which may provide an effective strategy for the treatment of SAP in the future.

重症胰腺炎（SAP）严重危害着人类健康，巨噬细胞激活在其演进中发挥着重要作用。近年来，脱细胞基质材料受到再生医学研究者的青睐，研究表明其可调控细胞行为从而促进组织修复，然而其在胰腺损伤修复中的作用及机制尚不清楚。我们发现胰腺胞外基质（ECM）水凝胶可减轻SAP损伤，且损伤区域见大量的M2型巨噬细胞，我们还发现炎性相关miRNA在SAP演进过程中发挥重要的作用。据此，本项目拟先制备大鼠胰腺ECM水凝胶，并评价其理化性能及生物相容性；然后将其胰腺内注射于大鼠SAP，研究其对腺泡细胞的存活和巨噬细胞表型极化的规律，明确其对SAP损伤的修复作用；并且通过体内干预巨噬细胞以及体外模拟局部炎症模型，明确巨噬细胞极化在修复SAP损伤中的作用；最后通过miRNA芯片、Real-time PCR和干预等手段，揭示特异性miRNA在水凝胶调控巨噬细胞极化中的作用，这可为未来胰腺疾病的治疗提供一种有效手段。

近年来，脱细胞基质材料受到再生医学研究者的青睐，研究表明其可调控细胞行为从而促进组织修复，然而其在胰腺损伤修复中的作用及机制尚不清楚。本项目围绕胰腺基质水凝胶诱导巨噬细胞M2型极化减轻重症急性胰腺炎（SAP）损伤的机制展开了一系列研究，经过实验探索，取得了以下研究成果：（1）成功研制出胰腺ECM水凝胶并对其进行了理化性能表征和生物相容性评价，研究发现该ECM水凝胶通过诱导胰腺损伤部位的M2型巨噬细胞极化，进而发挥胰腺损伤保护作用；（2）建立了胎盘间充质干细胞分离培养的优化体系，并揭示其通过高表达TSG-6诱导M2型巨噬细胞极化、改善胰腺炎损伤的机制；（3）探究了胰腺ECM水凝胶联合间充质干细胞治疗SAP的协同作用及其机制，证实其通过分泌TSG-6抑制STAT3和NF-κB信号通路，调控巨噬细胞M2型极化进而减轻SAP胰腺损伤。（4）发现circRNA在胰腺炎组织中的转录谱改变，同时构建出m6A circRNAs- miRNA以及lncRNA/circRNA- miRNA-mRNA分子网络。相关研究有望为未来SAP疾病的治疗提供一种新的治疗策略。