Journal Article

Diminished immune cell adhesion in hypoimmune ICAM-1 knockout human pluripotent stem cells

Holm, Alexis M., Saha, Sayandeep, Haynes, W. John, Del Rio, Natalia M., Kamp, Timothy J., Steill, John, Stewart, Ron, Seo, Jiwon, Blashka, Wesley, Murphy, Lydia, Zhang, Jue, Henrichs, Abigale, Flannagan, Lauryn, Brown, Matthew E., Pimentel, Mireya, Huang, Liupei, Suresh Babu, Jayalaxmi, Scholz, Merrick J., Young, Elizabeth E., Kratz, Jeremy

2025

Overview

Gene edited human pluripotent stem cells are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive immune responses, but have largely not addressed the innate immune cells, such as neutrophils, that mediate inflammation and rejection processes occurring early after graft transplantation. We identify the adhesion molecule ICAM-1 as a hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In our experiments, we find that ICAM-1 blocking or knockout in human pluripotent stem cell-derived cardiovascular therapies imparts significantly diminished binding of multiple immune cell types. ICAM-1 knockout results in diminished T cell proliferation and activation responses in vitro and in longer in vivo retention/protection of knockout grafts following immune cell encounter in NeoThy humanized mice. We also introduce the ICAM-1 knockout edit into existing first-generation hypoimmune human pluripotent stem cells and prevent immune cell binding. This promising hypoimmune editing strategy has the potential to improve transplantation outcomes for regenerative therapies in the setting of cardiovascular pathologies and several other diseases. Hypoimmune gene editing in human pluripotent stem cells (hPSCs) provides a promising platform for cellular therapies. Here, the authors report that CRISPR mediated deletion of ICAM-1 in hPSC-derived grafts reduces immune cell adhesion, dampens T cell activation, and protects against immune rejection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/100 / 13/106 / 13/31 / 13/51 / 38 / 38/39 / 38/91 / 42 / 45 / 59 / 59/5 / 631/208/4041/3196 / 631/250/2161 / 631/532/2064 / Adaptive immunity / Adhesion / Animals / Antibodies / Binding / Cardiomyocytes / Cell activation / Cell adhesion / Cell adhesion & migration / Cell Adhesion - genetics / Cell Adhesion - immunology / Cell Proliferation / Cell therapy / CRISPR / CRISPR-Cas Systems / Editing / Fibroblasts / Gene Editing / Gene Knockout Techniques / Genes / Genetic modification / Genome editing / Graft rejection / Graft Rejection - immunology / Grafting / Humanities and Social Sciences / Humans / Immune system / Immunity, Innate / Innate immunity / Intercellular adhesion molecule 1 / Intercellular Adhesion Molecule-1 - genetics / Intercellular Adhesion Molecule-1 - immunology / Intercellular Adhesion Molecule-1 - metabolism / Leukocytes (neutrophilic) / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / Pluripotency / Pluripotent Stem Cells - immunology / Pluripotent Stem Cells - metabolism / Proteins / Rejection / Science / Science (multidisciplinary) / Stem cells / T-Lymphocytes - immunology / Transplantation / Transplants & implants / Xenografts