Development of immunocompatible pluripotent stem cells via CRISPR-based human leukocyte antigen engineering

Abstract

Pluripotent stem cell transplantation is a promising regenerative strategy for treating intractable diseases. However, securing human leukocyte antigen (HLA)-matched donor stem cells is extremely difficult. The traditional approach for generating such cells is to establish homozygous pluripotent stem cell lines. Unfortunately, because of HLA diversity, this strategy is too time-consuming to be of practical use. HLA engineering of donor stem cells has been proposed recently as a means to evade graft-versus-host rejection in stem cell allotransplantation. This approach would be advantageous in both time and cost to the traditional method, but its feasibility must be investigated. In this study, we used CRISPR/Cas9 to knockout HLA-B from inducible pluripotent stem cells (iPSCs) with heterogenous HLA-B and showed that the HLA-B knockout iPSCs resulted in less immunogenicity in HLA-B antisera than that in the control. Our results support the feasibility of HLA-engineered iPSCs in stem cell allotransplantation. Blocking the expression of genes that regulate the immune response in therapeutic stem cells could increase the chances of success following transplantation. Discrepancies between human leukocyte antigen (HLA) genes in a patient and those in transplanted stem cells can cause a damaging immune response and transplantation failure, yet matching HLA types between donors and recipients is notoriously difficult. Ji Hyeon Ju at The Catholic University of Korea in Seoul and colleagues have used the CRISPR/Cas9 gene editing system to introduce a mutation in the HLA-B gene that prevents its expression in pluripotent stem cells derived from adult cells. These modified cells not only retain their capacity to self-renew and differentiate, they are also less likely to trigger an immune response. This promising new approach could reduce the time and cost of developing effective stem cell therapies.