| Autor: |
Elad Sintov, Igor Nikolskiy, Victor Barrera, Jennifer Hyoje-Ryu Kenty, Alexander S. Atkin, Dario Gerace, Shannan J. Ho Sui, Kyle Boulanger, Douglas A. Melton |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Stem Cell Reports. 17:1976-1990 |
| ISSN: |
2213-6711 |
| DOI: |
10.1016/j.stemcr.2022.08.002 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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