Title: ICAM-1 knockout pluripotent stem cell-derived endothelial cells as a hypoimmune vascular cellular therapy
Abstract: Human pluripotent stem cell (PSC)-derived endothelial cells (ECs) hold great promise for vascularized regenerative cell therapies, but immune allograft rejection remains a major hurdle. In both solid organ transplants and multi-cellular vascularized PSC-derived grafts, ECs form the first point of contact with the recipient’s immune system and are critical mediators of immune rejection. To mitigate this response, gene editing approaches can be used to create hypoimmune ECs by knocking out (KO) key immune-associated genes. However, for clinical translation, it is critical to ensure that gene-edited ECs retain functional stability and key vascular properties. This study evaluates a novel hypoimmune platform, using PSC-derived ECs in which intercellular adhesion molecule-1 (ICAM-1), a key regulator of immune synapse formation and leukocyte trafficking, is ablated. ICAM-1 is highly expressed on ECs and facilitates adhesion, transmigration, and activation of immune cells, particularly during inflammation at the transplant site. ICAM-1 ablation may significantly enhance graft survival by reducing leukocyte adherence and immune-mediated destruction. Our in vitro data show that ICAM-1 KO PSC-ECs significantly reduce leukocyte adhesion and cytotoxic T cell proliferation compared to its wild-type counterpart. To assess the translational potential of this approach, we investigate whether ICAM-1 KO PSC-ECs retain essential vascular functions. In parallel, we use a physiologically relevant 3D model to examine how these cells interact with neutrophils during transendothelial migration, a critical process in early graft inflammation and acute rejection. Together, this work establishes that targeting ICAM-1 is a promising strategy to engineer immune evasive vasculature that can potentially overcome the hurdles of allograft rejection, for regenerative transplantation.
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