Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets
Open accessAbstract
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.
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scRNA-seq and a CRISPR screen of SC-islets transplanted into a humanized mouse model revealed that SC-islets upregulated genes in the interferon (IFN) pathway during graft rejection.
“Lastly, in a unique approach, scRNA-seq and a CRIPSR screen of SC-islets transplanted into a humanized mouse model revealed that SC-islets upregulated genes in the interferon (IFN) pathway during graft rejection.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [121]
Knockout of CXCL10 improved survival during allogeneic transplantation in humanized mice.
“Knockout of CXCL10, which is induced by IFN signaling and appeared to be essential for early IFN-triggered immune responses in transplanted SC-islets, improved survival during allogeneic transplantation in humanized mice.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [121]
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- Authors
- Sintov, E., Nikolskiy, I., Barrera, V., Hyoje-Ryu Kenty, J., Atkin, A. S., Gerace, D., Ho Sui, S. J., Boulanger, K., & Melton, D. A.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sintov, Elad
- Melton, Douglas A.
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 17
- Issue
- 9
- Pages
- 1976-1990
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC9481918
- OpenAlex
- W4294190626
- Cited by
- 45
- References
- 75
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 10 · 2023: 14 · 2022: 2
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Harvard Stem Cell Institute
- Harvard Medical School
- Juvenile Diabetes Research Foundation United States of America (3-PDF-2018-590-A-N)
- Leona M. and Harry B. Helmsley Charitable Trust (5-SRA-2014-284-Q-R)
- Broad Institute
- Harvard University
- JPB Foundation (1094)
- Harvard University Harvard Catalyst
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- stem cell-derived islets, allograft rejection, immune rejection, interferon-gamma, interferon pathway, CXCL10, genome editing, CRISPR screen, type 1 diabetes, islet transplantation, humanized mice, islet graft survival, autoimmunity
- MeSH terms
- Human Embryonic Stem Cells, Animals, Humans, Islets of Langerhans, Leukocytes, Mononuclear, Islets of Langerhans Transplantation, Mice, Clustered Regularly Interspaced Short Palindromic Repeats
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