TREM2阳性巨噬细胞促进胆道闭锁的胆管反应和肝纤维化机制及其干预策略研究

发育期的肝胆损伤可诱发胆管反应和肝纤维化，抑制肝脏生长再生。过往研究大多集中在成人期，对发育期肝胆损伤修复机制认识甚少。发育期的研究对理解肝脏发育、损伤和再生修复有着重要意义。胆道闭锁是这一时期经典肝胆疾病，表现为显著胆管反应和肝纤维化，是儿童肝移植最主要的诱因。项目前期通过单细胞RNA测序，鉴定包括免疫细胞、胆管细胞和肝成纤维细胞在内的主要细胞类型，并发现一群高度富集的TREM2阳性巨噬细胞；深入的生物信息分析和体外细胞实验提示，TREM2阳性巨噬细胞通过AREG-EGFR和TNFSF12-TNFRSF12A作用于胆管细胞和成纤维细胞，促进胆管反应和肝纤维化；疾病小鼠模型结果显示，Trem2敲除和阻断TNFRSF12A均显著抑制胆道闭锁，降低肝纤维化和胆管反应水平。下一步，我们将深入研究TREM2阳性巨噬细胞作用分子细胞机制，并建立靶向胆管反应和肝纤维化的双靶向策略，促进肝脏生长再生。

Liver and biliary injury during development can induce ductular reaction and liver fibrosis, which suppresses liver growth and regeneration. Previous studies focus mainly on adult. However, the mechanisms of liver injury and repair in children are largely unknown. Therefore, studies in children are meaningful in understanding liver growth, injury, regeneration and repair. Biliary atresia (BA) is a devastating neonatal liver disease, which displays significant ductular reaction and liver fibrosis. It is the most common indication for liver transplant in children. Our preliminary single cell RNA sequencing result identified major cell types including immune cells, cholangiocytes and fibroblasts, and a enriched group of TREM2 positive macrophages in the liver of BA. In-depth bioinformatics analyes and cell assay suggested that these macrophages interacted with cholangiocytes and fibroblasts through AREG-EGFR and TNFSF12-TNFRSF12A pathways, promoting ductular reaction and liver fibrosis. Moreover, in experimentally induced BA mice, both knockout of Trem2 and blockage of TNFRSF12A suppressed biliary atresia, reduced liver fibrosis and ductular reaction. Next, we will investigate the detailed molecular and cellular mechanisms of TREM2 positive macrophages and will develop a double hit strategy for targeting ductular reaction and liver fibrosis simultaneously, which facilitates liver growth and regeneration.