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

Sayandeep Saha, W. John Haynes, Jiwon Seo, Natalia M. Rio, Elizabeth E. Young, Jue Zhang, Alexis M. Holm, Mireya Pimentel, Lauryn Flannagan, Liupei Huang, Wesley Blashka, Lydia Murphy, Merrick J. Scholz, Abigale Henrichs, Jayalaxmi Suresh Babu, John Steill, Jeremy Kratz, Ron Stewart, Timothy J. Kamp and Matthew E. Brown ()
Additional contact information
Sayandeep Saha: Department of Surgery
W. John Haynes: Department of Surgery
Jiwon Seo: Department of Surgery
Natalia M. Rio: Department of Surgery
Elizabeth E. Young: Department of Surgery
Jue Zhang: Morgridge Institute for Research
Alexis M. Holm: Department of Surgery
Mireya Pimentel: Department of Surgery
Lauryn Flannagan: Department of Medicine
Liupei Huang: Department of Surgery
Wesley Blashka: Department of Surgery
Lydia Murphy: Department of Surgery
Merrick J. Scholz: Department of Surgery
Abigale Henrichs: Department of Surgery
Jayalaxmi Suresh Babu: Johns Hopkins Bloomberg School of Public Health
John Steill: Morgridge Institute for Research
Jeremy Kratz: Department of Medicine
Ron Stewart: Morgridge Institute for Research
Timothy J. Kamp: Department of Medicine
Matthew E. Brown: Department of Surgery

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62568-2

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