Human embryonic stem cells (hESCs) hold promise in regenerative medicine but allogeneic immune rejections caused by highly polymorphic human leukocyte antigens (HLAs) remain a barrier to their clinical applications. Here, we used a CRISPR/Cas9-mediated HLA-editing strategy to generate a variety of HLA homozygous-like hESC lines from pre-established hESC lines. We edited four pre-established HLA-heterozygous hESC lines and created a mini library of 14 HLA-edited hESC lines in which single HLA-A and HLA-B alleles and both HLA-DR alleles are disrupted. The HLA-edited hESC derivatives elicited both low T cell- and low NK cell-mediated immune responses. Our library would cover about 40% of the Asian-Pacific population. We estimate that HLA-editing of only 19 pre-established hESC lines would give rise to 46 different hESC lines to cover 90% of the Asian-Pacific population. This study offers an opportunity to generate an off-the-shelf HLA-compatible hESC bank, available for immune-compatible cell transplantation, without embryo destruction.

人类胚胎干细胞 (hESCs) 在再生医学中具有前景，但由高度多态性人类白细胞抗原 (HLA) 引起的同种异体免疫排斥仍然是其临床应用的障碍。在这里，我们使用 CRISPR/Cas9 介导的 HLA 编辑策略从预先建立的 hESC 系中生成各种 HLA 纯合样 hESC 系。我们编辑了四个预先建立的 HLA 杂合 hESC 系，并创建了一个包含 14 个 HLA 编辑的 hESC 系的小型文库，其中单个 HLA-A 和 HLA-B 等位基因以及两个 HLA-DR 等位基因都被破坏。HLA 编辑的 hESC 衍生物引发了低 T 细胞和低 NK 细胞介导的免疫反应。我们的图书馆将覆盖亚太地区约 40% 的人口。我们估计，仅 19 个预先建立的 hESC 系的 HLA 编辑将产生 46 个不同的 hESC 系，以覆盖 90% 的亚太人口。这项研究提供了一个机会来生成一个现成的 HLA 兼容的 hESC 库，可用于免疫兼容的细胞移植，而不会破坏胚胎。