Genetic manipulation of stress pathways can protect stem-cell-derived islets from apoptosis in vitro
Open accessAbstract
The in vitro production of stem-cell-derived islets (SC-islets) has brought forth the potential of transplanting these cells to restore glycemic control in people with diabetes. Nonetheless, alloimmune and autoimmune responses remain considerable challenges for a broad clinical implementation of β-cell replacement therapies. β-cell stress has been implicated in the onset of β-cell immunogenicity and death and is likely to contribute to β-cell failure following transplantation. We show that inducing stress and/or administering cytokines causes SC-islet apoptosis, cellular dysfunction, and an increased expression of β-cell stress- and immune-interaction-related genes. We then demonstrate that manipulating some of these genes results in enhanced protection of SC-islets from apoptosis in vitro.
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These gene knockdowns decreased T-cell activation and T-cell induced apoptosis when SC-islets were co-cultured with peripheral blood mononuclear cells.
“Furthermore, these gene knockdowns decreased T-cell activation and T-cell induced apoptosis when SC-islets were co-cultured with peripheral blood mononuclear cells.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [136]
The Results section ('Genetic manipulation increases protection of SC-islets from apoptosis mediated by allorecognition in vitro'; page not provided) reports reduced T-cell activation and fewer apoptotic SC-islets after gene knockdown and co-culture with allogeneic T1D PBMCs. It attributes the apoptosis to stress and allorecognition, but does not establish that T cells specifically induced it. (LLM, conf=0.82)
Experimental — accuracy not yet measuredWhile SC-islets appear to be generally more stress-resistant than isolated primary islets, they nevertheless respond to inflammatory cytokines with similar stress response pathways.
“Furthermore, while SC-islets appear to be generally more stress-resistant than isolated primary islets,136 they nevertheless respond to inflammatory cytokines with similar stress response pathways,137”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [136]
Lentiviral shRNA knockdown of XBP1, CDKN1A, NLRC5, and β2M decreased apoptosis in SC-islets treated with stressors and downregulated stress and immune interaction genes.
“Lentiviral shRNA knockdown of XBP1, CDKN1A, NLRC5, and β2M decreased the level of apoptosis in SC-islets when treated with these stressors as well as downregulated the expression of genes associated with stress responses and immune interaction.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [136]
SC-islets exhibited dysfunction, apoptosis, and increased expression of stress and immune interaction genes when exposed to a cytokine mix, thapsigargin, and high glucose.
“Specifically, SC-islets exhibited dysfunction, apoptosis, and increased expression of genes related to stress and immune interaction when exposed to a variety of stressors, including a cytokine mix to mimic inflammatory stress, thapsigargin to induce ER stress, and high glucose to replicate metabolic stress.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [136]
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- Authors
- Leite, N. C., Pelayo, G. C., & Melton, D. A.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Melton, Douglas A.
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 17
- Issue
- 4
- Pages
- 766-774
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC9023776
- OpenAlex
- W4214836757
- Cited by
- 36
- References
- 26
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 8
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- stem cell-derived islets, beta-cell apoptosis, beta-cell stress, islet transplantation, diabetes mellitus, cytokines, genetic engineering, beta cell replacement therapy, islet dysfunction, autoimmunity
- MeSH terms
- Humans, Islets of Langerhans, Cytokines, Islets of Langerhans Transplantation, Apoptosis, Insulin-Secreting Cells
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