{"id":"doi:10.1016/j.stemcr.2022.08.002","kind":"article","title":"Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets","authors":["Sintov E","Nikolskiy I","Barrera V","Hyoje-Ryu Kenty J","Atkin AS","Gerace D","Ho Sui SJ","Boulanger K","Melton DA"],"author_count":9,"year":2022,"published":"2022-09-01","venue":"Stem cell reports","cited_by":42,"doi":"10.1016/j.stemcr.2022.08.002","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.stemcr.2022.08.002","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.stemcr.2022.08.002","updated":null,"pmid":"36055241","pmcid":"PMC9481918","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC9481918/pdf","abstract":"Human embryonic stem cells (hESCs) provide opportunities for cell replacement therapy of insulin-dependent diabetes. Therapeutic quantities of human stem cell-derived islets (SC-islets) can be produced by directed differentiation. However, preventing allo-rejection and recurring autoimmunity, without the use of encapsulation or systemic immunosuppressants, remains a challenge. An attractive approach is to transplant SC-islets, genetically modified to reduce the impact of immune rejection. To determine the underlying forces that drive immunogenicity of SC-islets in inflammatory environments, we performed single-cell RNA sequencing (scRNA-seq) and whole-genome CRISPR screen of SC-islets under immune interaction with allogeneic peripheral blood mononuclear cells (PBMCs). Data analysis points to \"alarmed\" populations of SC-islets that upregulate genes in the interferon (IFN) pathway. The CRISPR screen in vivo confirms that targeting IFNγ-induced mediators has beneficial effects on SC-islet survival under immune attack. Manipulating the IFN response by depleting chemokine ligand 10 (CXCL10) in SC-islet grafts confers improved survival against allo-rejection compared with wild-type grafts in humanized mice. These results offer insights into the nature of immune destruction of SC-islets during allogeneic responses and provide targets for gene editing.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets\" by Sintov E, Nikolskiy I, Barrera V et al., https://doi.org/10.1016/j.stemcr.2022.08.002, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}