Hypoimmunogenic universal human iPSC-derived endothelial cells for immune evasion and blood flow restoration in humanized peripheral artery disease mouse model.

Peripheral arterial disease (PAD) is a leading cause of limb disability due to ischemia caused by atherosclerotic plaques. Cell-based therapies using endothelial cells (ECs) have shown promise in promoting angiogenesis for PAD, but challenges remain in obtaining sufficient ECs from human tissues. Induced pluripotent stem cells (iPSCs) provide a potential solution, though immune rejection issues arise due to HLA mismatches. The depletion of HLA class I and II through gene editing aims to broadly avoid lymphocyte recognition and can be achieved by inactivating B2M and CIITA. However, B2M inactivation can lead to a missing self killing response by natural killer (NK) cells and macrophages. To overcome this, we proposed universal iPSCs (U-iPSCs) by knocking out B2M and CIITA and over-expressing CD24 to reduce immune rejection.

外周动脉疾病（Peripheral arterial disease, PAD）是动脉粥样硬化斑块引发缺血进而导致肢体残疾的首要病因。采用内皮细胞（endothelial cells, ECs）的细胞疗法在促进外周动脉疾病血管生成方面已展现出应用前景，但从人体组织中获取足量内皮细胞仍存在挑战。诱导多能干细胞（induced pluripotent stem cells, iPSCs）为该问题提供了潜在解决方案，不过因人类白细胞抗原（Human Leukocyte Antigen, HLA）错配会引发免疫排斥问题。通过基因编辑敲除HLA I类和II类基因，可广泛避免淋巴细胞识别，该策略可通过失活B2M与CIITA基因实现。然而，B2M基因失活会诱发自然杀伤（natural killer, NK）细胞及巨噬细胞产生“丢失自我”的杀伤应答。为克服这一局限，本研究通过同时敲除B2M与CIITA基因并过表达CD24，构建了通用型诱导多能干细胞（U-iPSCs）以降低免疫排斥反应。