免疫介导胆道损伤所致的难治性胆道并发症是降低肝移植中长期生存率的首要原因。课题组在解决疾病早诊并以骨髓间充质干细胞（MSC）治疗的前期研究中发现，MSC能改善预后却难以逆转疾病，可能原因是MSC靶向病灶数量少影响疗效；同时缺乏精准的MSC活体示踪技术导致对其定位与功效探究不足。用基因修饰的方法实现MSC对病灶的靶向归巢及光声示踪有望解决难题。申请人发现肝移植后免疫损伤部位高表达趋化因子CXCL10，以其对应受体CXCR3为MSC归巢分子靶点，以能产生优质光声信号的酪氨酸激酶（Tyr）为报告基因，构建生物安全性好的 CXCR3/Tyr-mRNA修饰体系，获得兼顾特异靶向病灶和光声显像能力的MSC；探索具成像深度及灵敏度的光声成像方法，在提高疗效的同时监测MSC归巢效率，实现“归巢准，看得清”的目标，有望解决MSC基因修饰中生物安全性差、活体示踪中难以兼顾深度和灵敏度的难题，具临床转化前景。

Refractory bile complication caused by immune-mediated biliary injury represents the primary reason for reducing the long-term survival rate after liver transplantation. In our previous research, we successfully accomplished the diagnosis and treatment for the disease at early stage with bone marrow mesenchymal stem cells (MSC). Meanwhile, we found that even MSCs was of great benefit to the prognosis, it’s still difficult to reverse the disease process, which was mainly due to the limited MSCs targeting to the lesions. The insufficient therapeutic efficacy is attributed to the lack of an accurate live tracing technology to locate MSCs. Genetic modification for MSCs to enhance targeted homing and enable photoacoustic tracing is expected to solve the problem above. After a series of profiling, chemokine CXCL10 was confirmed highly expressed in the lesions after liver transplantation. Therefore, we select its receptor-CXCR3 as the homing molecular target of MSCs and tyrosine kinase (Tyr), capable of producing high quality photoacoustic signals as the report gene. Afterwards, we modify MSCs with mRNA CXCR3/Tyr dual-gene modification system, which shows both specific targeting ability to lesions, brilliant photoacoustic imaging ability and we establish photoacoustic tracing method with excellent imaging depth and sensitivity. Overall, we aim to improve MSCs' therapeutic efficacy and meanwhile monitor its homing ability. The expected achievement is to overcome the present limitations of insufficient MSCs chemotactic ability and issues of depth and sensitivity in MSC live tracing technique and ultimately to promote the clinical transformation of MSCs.