Cloaked stem cells evade immune rejection in mice, pointing to a potential universal donor cell line

A study published in Stem Cell Reports demonstrates that genetically engineered human pluripotent stem cells (hPSCs) can overcome immune rejection in mice with humanized immune systems, surviving for five months in a stringent transplantation model. The findings provide proof-of-principle for the development of a potential universal donor hPSC line designed to resist immune attack.

Led by Danny Chan, University of Hong Kong, China, and Andras Nagy, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada, the research team inserted eight immunosuppressive genes into a single hPSC line to render the cells resistant to immune rejection.

When transplanted under the skin of mice reconstituted with a human immune system, unmodified hPSCs were rapidly rejected due to immunological mismatch.

In contrast, the engineered cells survived until the end of the five-month experiment, effectively demonstrating that the cells were “cloaked” from immune recognition—even in the highly immunoreactive environment of the skin.

To enhance safety, the researchers incorporated an additional gene that renders the cells susceptible to a specific drug, enabling their elimination if unwanted growth occurs. This “SafeCell” switch was tested in the mouse model and successfully halted the growth of the transplanted cells.

As hPSC-derived cell therapies move into the clinic, including recent trials targeting Parkinson’s disease and type I diabetes, immune rejection remains a major challenge. While autologous (patient-specific) hPSCs can reduce immune incompatibility, generating individualized cell products is time-consuming and costly.

Genetic engineering strategies such as the one demonstrated in this study offer an alternative approach.

Although these results establish proof-of-principle that engineered universal donor hPSCs can evade immune responses in a preclinical model, further studies will be required to evaluate the long-term efficacy and safety of such cell products in future preclinical and clinical settings.