Journal
STEM CELLS
Volume 35, Issue 5, Pages 1154-1161Publisher
WILEY
DOI: 10.1002/stem.2568
Keywords
Human embryonic stem cells; Immune protection; Cancer risk; Suicidal genes; Humanized mice
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Funding
- Chinese Ministry of Science and Technology [2012CB966900]
- National High-tech R&D Program (863 Program) [2015AA020310]
- National Natural Science Foundation of China [81372494, 815300045, 81373166, 81430032]
- Guangzhou Key Laboratory of Tumor Immunology Research
- Guangdong Province Key Special Science and Technology Project [2015B020225004]
- California Institute for Regenerative Medicine [RT3-07899]
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Human embryonic stem cells (hESCs) hold great promise in the regenerative therapy of many currently untreatable human diseases. One of the key bottlenecks is the immune rejection of hESC-derived allografts by the recipient. To overcome this challenge, we have established new approaches to induce immune protection of hESC-derived allografts through the coexpression of immune suppressive molecules CTLA4-Ig and PD-L1. However, this in turn raises a safety concern of cancer risk because these hESC-derived cells can evade immune surveillance. To address this safety concern, we developed a safety checkpoint so that the immune evasive hESC-derived cells in the graft can be effectively eliminated if any cellular transformation is detected. In this context, we knock-in the suicidal gene herpes simplex virus thymidine kinase (HSVTK) into the constitutive HPRT locus of CP hESCs (knock-in hESCs expressing CTLA4-Ig and PD-L1), denoted CPTK hESCs. Employing humanized mice (Hu-mice) reconstituted with human immune system, we demonstrated that the CPTK hESC-derived cells are protected from immune rejection. In addition, CPTK hESC-derived cells can be efficiently eliminated in vitro and in vivo with FDA approved TK-targeting drug ganciclovir. Therefore, this new safety checkpoint improves the feasibility to use the immune evasive hESC-derived cells for regenerative medicine. Stem Cells2017;35:1154-1161
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