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.