Generation of universal and hypoimmunogenic human pluripotent stem cells

There is a need to store very large numbers of conventional human pluripotent stem cell (hPSC) lines for their off‐the‐shelf usage in stem cell therapy. Therefore, it is valuable to generate “universal” or “hypoimmunogenic” hPSCs with gene‐editing technology by knocking out or in immune‐related genes. A few universal or hypoimmunogenic hPSC lines should be enough to store for their off‐the‐shelf usage. Here, we overview and discuss how to prepare universal or hypoimmunogenic hPSCs and their disadvantages. β2‐Microglobulin‐knockout hPSCs did not harbour human leukocyte antigen (HLA)‐expressing class I cells but rather activated natural killer (NK) cells. To avoid NK cell and macrophage activities, homozygous hPSCs expressing a single allele of an HLA class I molecule, such as HLA‐C, were developed. Major HLA class I molecules were knocked out, and PD‐L1, HLA‐G and CD47 were knocked in hPSCs using CRISPR/Cas9 gene editing. These cells escaped activation of not only T cells but also NK cells and macrophages, generating universal hPSCs. To avoid natural killer (NK) cell and macrophage activities, homozygous human pluripotent stem cells (hPSCs) expressing a single allele of an HLA class Ia molecule, such as HLA‐C, were developed (left picture). Major HLA class I molecules were knocked out and PD‐L1, HLA‐G and CD47 were knocked in hPSCs using CRISPR/Cas9 gene editing (right picture). These cells escaped activation of not only T cells but also NK cells and macrophages, generating universal hPSCs.