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Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance
Dario Gerace1, Quan Zhou1, Jennifer Hyoje-Ryu Kenty1
1Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA.
Cell Reports. Medicine
|January 4, 2023
Summary
Generating immune-evasive stem cell-derived islet cells without immunosuppression is challenging. Engineering these cells to secrete specific cytokines promotes a tolerogenic environment, preventing rejection and correcting diabetes in mice.
Area of Science:
- Immunology
- Regenerative Medicine
- Transplantation Biology
Background:
- Achieving immunological protection for transplanted stem cell-derived islet (SC-islet) cells without chronic immunosuppression or encapsulation remains a significant hurdle.
- Current genetic engineering strategies for immune-evasive SC-islet cells have yielded inconsistent outcomes.
- Targeting human leukocyte antigens (HLAs) and PD-L1 alone has proven insufficient to prevent xenograft (xeno) or allograft (allo)-rejection of SC-islet cells.
Purpose of the Study:
- To develop a novel strategy for immune evasion of SC-islet cells.
- To investigate the potential of engineering SC-islet cells to create a tolerogenic microenvironment.
- To assess the efficacy of cytokine-secreting SC-islet cells in preventing graft rejection and correcting diabetes.
Main Methods:
- Genetically engineered human embryonic stem cells (hESCs) to differentiate into SC-islet cells.
- Engineered SC-islet cells to secrete interleukin-10 (IL-10), transforming growth factor β (TGF-β), and modified IL-2.
- Transplanted engineered SC-islet cells into non-obese diabetic (NOD) mice.
- Evaluated graft survival, immune rejection, and diabetes correction.
Main Results:
- Engineered SC-islet cells secreting IL-10, TGF-β, and modified IL-2 resisted xeno-rejection in NOD mice.
- The cytokine secretion promoted a tolerogenic local microenvironment by recruiting regulatory T cells (Tregs).
- Transplanted cells corrected diabetes for up to 8 weeks post-transplantation.
Conclusions:
- Genetically engineering SC-islet cells to secrete specific cytokines is a promising approach to induce a tolerogenic microenvironment.
- This strategy offers a potential solution for cell replacement therapy in diabetes without requiring encapsulation or immunosuppression.
- This method represents a significant advancement in overcoming immunological barriers in islet transplantation.
