Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets

Sintov, Elad; Nikolskiy, Igor; Barrera, Víctor; Kenty, Jennifer Hyoje-Ryu; Atkin, Alexander S.; Gerace, Dario; Sui, Shannan Ho; Boulanger, Kyle; Melton, Douglas A.

doi:10.1016/j.stemcr.2022.08.002

Cited by 29 publications

(23 citation statements)

References 76 publications

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“…Increased efficacy of generation or purification of progenitors have also been pursued to generate SC-islets 10,52,67,68 . Furthermore, genetic engineering to lessen immune recognition 69 of SC-islets in order to transplant the cells without immunosuppression has been reported 62,70 . SC-islets have been generated from patients with diabetes for study of diabetes pathology and consideration as an autologous cell source of diabetes regenerative medicine 12,[71][72][73][74][75][76] .…”

Section: Discussionmentioning

confidence: 99%

Defining the chromatin and transcriptional landscape of stem cell-derived islets

Augsornworawat

Hogrebe²,

Ishahak

et al. 2022

Preprint

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Insulin-secreting β-cells within the pancreatic islets of Langerhans are lost in patients with type 1 diabetes1. Islets can be generated in vitro by differentiation of human pluripotent stem cells2-5, but understanding of the molecular events governing this process is limited. Here, we use single-cell multiomics to measure chromatin accessibility and transcriptional profiles of 120,064 cells to characterize and delineate maturation of islets from in vitro differentiation. We find distinguishing chromatin accessibility and gene expression signatures as well as dynamic profiles for each major islet cell type produced from in vitro differentiation. Furthermore, based on chromatin accessibility, β, α, and δ cells from in vitro differentiation are more ambiguous in their cellular identity than from isolated primary islets. However, extended time in vitro or with transplantation into mice drives more distinct states of chromatin accessibility for each cell type. Modulation of CTCF expression redirects cell fate from pancreatic islet endocrine to an intestinal enteroendocrine-like cell type. Additionally, knockdown of ARID1B enhances β-cell maturation transcriptionally and by chromatin accessibility. These results provide a comprehensive atlas and insights into cell fate identity and maturation of stem cell-derived islets, which will inform on their utility for therapy and disease modeling6-8.

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Section: Discussionmentioning

confidence: 99%

Defining the chromatin and transcriptional landscape of stem cell-derived islets

Augsornworawat

Hogrebe²,

Ishahak

et al. 2022

Preprint

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show abstract

“…A limitation of conducting screens using the mouse system is that there are known differences between mouse and human β cells and immunological contexts( 120 ). Addressing this limitation, a human SCDIs transplantation survival screen has also been conducted( 121 ). Human SCDIs were transplanted into Hu-PBL-NSG-MHC null mice that also received human PBMCs.…”

Section: Future Prospects: Genetic Screensmentioning

confidence: 99%

Genetic Engineering of Immune Evasive Stem Cell-Derived Islets

et al. 2022

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Genome editing has the potential to revolutionize many investigative and therapeutic strategies in biology and medicine. In the field of regenerative medicine, one of the leading applications of genome engineering technology is the generation of immune evasive pluripotent stem cell-derived somatic cells for transplantation. In particular, as more functional and therapeutically relevant human pluripotent stem cell-derived islets (SCDI) are produced in many labs and studied in clinical trials, there is keen interest in studying the immunogenicity of these cells and modulating allogeneic and autoimmune immune responses for therapeutic benefit. Significant experimental work has already suggested that elimination of Human Leukocytes Antigen (HLA) expression and overexpression of immunomodulatory genes can impact survival of a variety of pluripotent stem cell-derived somatic cell types. Limited work published to date focuses on stem cell-derived islets and work in a number of labs is ongoing. Rapid progress is occurring in the genome editing of human pluripotent stem cells and their progeny focused on evading destruction by the immune system in transplantation models, and while much research is still needed, there is no doubt the combined technologies of genome editing and stem cell therapy will profoundly impact transplantation medicine in the future.

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“… 12 , 13 More recently, genetic engineering of SC-islets to evade immune recognition has been attempted. 14 , 15 , 16 While this is a promising alternative, current engineering strategies are limited by transgene silencing and recurrent immune rejection. 17 , 18 , 19 Here, we generated immune-evasive SC-islet cells that over-express PD-L1 and the human leukocyte antigen (HLA)-E long-chain fusion from the constitutively expressed GAPDH locus in both HLA-competent and -deficient settings.…”

Section: Introductionmentioning

confidence: 99%

Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets

Cited by 29 publications

References 76 publications

Defining the chromatin and transcriptional landscape of stem cell-derived islets

Defining the chromatin and transcriptional landscape of stem cell-derived islets

Genetic Engineering of Immune Evasive Stem Cell-Derived Islets

Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance

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