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CRISPR Screening to Investigate Stem Cell-Derived Islets

ABSTRACT: Genetically engineering human pluripotent stem cell (hPSC)-derived islets is a promising strategy for improving transplantation for diabetes cell therapy. However, genetic perturbations for improving transplantation efficacy have yet to be elucidated. To identify potential targets, we performed an unbiased whole-genome CRISPR-activation screen in transplanted stem cell-derived islets (SC-islets). We first created a stem cell line with CRISPR-activation components (HUES8-VPR). We transduced the HUES8-VPR stem cells with a lentiviral guide RNA library targeting the whole human genome. These transduced stem cells were differentiated into SC-islets, transplanted into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) immunodeficient mice, and then extracted for next-generation sequencing. The screen identified multiple candidates, including the Fc alpha/mu receptor (FCAMR). In vitro characterization revealed that FCAMR overexpression did not negatively affect SC-islet function or transcriptomic identity. Mice transplanted with SC-islets overexpressing FCAMR had increased blood glucose levels and increased cpeptide compared to controls. Furthermore, mice receiving FCAMR-modified grafts maintained a higher body weight compared to controls in a diabetic setting. Our study utilizes a screening approach to identify potential candidates for improving SC-islet therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305932 | GEO | 2026/05/20

REPOSITORIES: GEO

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