Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance
Summary
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 (Tregs) 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. Copyright © 2022. Published by Elsevier Inc.
| Authors | Gerace D, Zhou Q, Kenty JH, Veres A, Sintov E, Wang X, Boulanger KR, Li H, Melton DA |
|---|---|
| Journal | Cell reports. Medicine |
| Publication Date | 2023 Jan 17;4(1):100879 |
| PubMed | 36599351 |
| PubMed Central | PMC9873825 |
| DOI | 10.1016/j.xcrm.2022.100879 |