An Ju-Hyun, Koh Hyebin, Ahn Yujin, Kim Jieun, Han A-Reum, Lee Ji Yoon, Kim Sun-Uk, Lee Jong-Hee
Futuristic Animal Resource and Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, South Korea.
Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, South Korea.
Front Bioeng Biotechnol. 2022 Jul 22;10:936584. doi: 10.3389/fbioe.2022.936584. eCollection 2022.
Universally acceptable donor cells have been developed to address the unmet need for immunotypically matched materials for regenerative medicine. Since forced expression of hypoimmunogenic genes represses the immune response, we established universal pluripotent stem cells (PSCs) by replacing endogenous β2-microglobulin (β2m) with β2m directly conjugated to human leukocyte antigen (HLA)-G, thereby simultaneously suppressing HLA-I expression and the natural killer (NK) cell-mediated immune response. These modified human PSCs retained their pluripotency and differentiation capacity; however, surface presentation of HLA-G was absent from subsequently differentiated cells, particularly cells of neural lineages, due to the downregulation of antigen processing and presentation machinery (APM) genes. Induction of APM genes by overexpression of NLR-family CARD domain-containing 5 (NLRC5) or activator subunit of nuclear factor kappa B (NF-κB) heterodimer (RelA) recovered the surface expression of HLA-G and the hypoimmunogenicity of neural cells. Our findings enhance the utility of hypoimmunogenic cells as universal donors and will contribute to the development of off-the-shelf stem-cell therapeutics.
为满足再生医学中对免疫型匹配材料尚未满足的需求，已开发出普遍可接受的供体细胞。由于低免疫原性基因的强制表达会抑制免疫反应，我们通过用人白细胞抗原（HLA）-G直接偶联的β2微球蛋白（β2m）替代内源性β2m，建立了通用多能干细胞（PSC），从而同时抑制HLA-I表达和自然杀伤（NK）细胞介导的免疫反应。这些经过修饰的人PSC保留了它们的多能性和分化能力；然而，由于抗原加工和呈递机制（APM）基因的下调，随后分化的细胞，特别是神经谱系的细胞中缺乏HLA-G的表面呈递。通过过表达含NLR家族CARD结构域5（NLRC5）或核因子κB（NF-κB）异二聚体（RelA）的激活亚基来诱导APM基因，可恢复HLA-G的表面表达和神经细胞的低免疫原性。我们的研究结果提高了低免疫原性细胞作为通用供体的实用性，并将有助于现成干细胞疗法的开发。
