Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance
Open accessAbstract
Immunological protection of transplanted stem cell-derived islet (SC-islet) cells is yet to be achieved without chronic immunosuppression or encapsulation. Existing genetic engineering approaches to produce immune-evasive SC-islet cells have so far shown variable results. Here, we show that targeting human leukocyte antigens (HLAs) and PD-L1 alone does not sufficiently protect SC-islet cells from xenograft (xeno)- or allograft (allo)-rejection. As an addition to these approaches, we genetically engineer SC-islet cells to secrete the cytokines interleukin-10 (IL-10), transforming growth factor β (TGF-β), and modified IL-2 such that they promote a tolerogenic local microenvironment by recruiting regulatory T cells (T regs ) to the islet grafts. Cytokine-secreting human SC-β cells resist xeno-rejection and correct diabetes for up to 8 weeks post-transplantation in non-obese diabetic (NOD) mice. Thus, genetically engineering human embryonic SCs (hESCs) to induce a tolerogenic local microenvironment represents a promising approach to provide SC-islet cells as a cell replacement therapy for diabetes without the requirement for encapsulation or immunosuppression.
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SC-islets can be genetically engineered to both remove antigens that would signal them for destruction by the host immune system and add surface signaling molecules that induce immune tolerance.
“Alternatively, the SC-islets themselves can be genetically engineered to both remove antigens that would signal them for destruction by the host immune system as well as add surface signaling molecules that induce immune tolerance.54,55”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [54]
The Results section, ‘Engineering immune-evasive SC-islet cells’ (page unavailable), describes SC-islets engineered to lack HLA class I antigens and express surface PD-L1. But those cells were rejected in the paper’s xenograft model; the localized tolerance reported in the Results and Discussion came from engineered secretion of cytokines, not from added surface signaling molecules. The claim therefore combines two approaches while overstating what the surface-molecule approach achieved. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPD-L1 alone was not sufficient to protect against xeno- and allorejection in transplanted SC-islets.
“For example, in contrast to prior studies, it was recently reported that PD-L1 alone was not sufficient to protect against xeno- and allorejection in transplanted SC-islets.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [54]
The Results (Engineering immune-evasive SC-islet cells; page unavailable) report that PD-L1 overexpression did not protect transplanted SC-islets from xenorejection in the authors’ mouse model. The paper does not establish the same result for transplanted allografts; the Discussion says PD-L1 may still be useful in an allogeneic setting. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSC-islets engineered to secrete IL-2 mutein, IL-10, and TGF-β reversed diabetes and survived for at least 8 weeks in an autoimmune diabetes mouse model.
“These cells reversed diabetes and survived for at least 8 weeks in an autoimmune diabetes mouse model.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [54]
HLA depletion facilitated improved cell survival in transplanted SC-islets.
“Instead, they reported HLA depletion facilitated improved cell survival.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [54]
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- Authors
- Gerace, D., Zhou, Q., Kenty, J. H.-R., Veres, A., Sintov, E., Wang, X., Boulanger, K. R., Li, H., & Melton, D. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Melton, Douglas A.
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 4
- Issue
- 1
- Pages
- 100879
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC9873825
- OpenAlex
- W4313528743
- Cited by
- 88
- References
- 67
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 22 · 2023: 15
- FWCI
- 23.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- OPUS - Open Publications of UTS Scholars (University of Technology Sydney) (submittedVersion, other-oa)
- Funders
- JPB Foundation (1094)
- Harvard Stem Cell Institute (DP-0180-18-02)
- Juvenile Diabetes Research Foundation United States of America (5-COE-2020-967-M-N)
- Harvard University
- 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 › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- stem cell-derived islets, immune rejection, immune tolerance, human embryonic stem cells, PD-L1, IL-10, TGF-beta, regulatory T cells, xenograft rejection, allograft rejection, NOD mice
- MeSH terms
- Animals, Humans, Immune Tolerance, Islets of Langerhans, Stem Cells, Cytokines, Mice, Inbred NOD, Mice, Cell Engineering
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