Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku, Tokyo 100-0004, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan; Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan.
Stem Cell Reports. 2023 Apr 11;18(4):985-998. doi: 10.1016/j.stemcr.2023.02.008. Epub 2023 Mar 23.
The testis is an immune-privileged organ. It is considered that the testis somatic microenvironment is responsible for immune suppression. However, immunological properties of spermatogonial stem cells (SSCs) have remained unknown. Here, we report the birth of allogeneic offspring by enhanced expression of immunosuppressive PD-L1 in SSCs. In vitro supplementation of GDNF and FGF2 increased expression of PD-L1 in SSCs. Cultured SSCs maintained allogeneic spermatogenesis that persisted for >1 year. However, depletion or gene editing of Pd-l1 family genes in SSCs prevented allogeneic spermatogenesis, which suggested that germ cells are responsible for suppression of the allogeneic response. PD-L1 was induced by activation of the MAPK14-BCL6B pathway, which drives self-renewal by reactive oxygen species (ROS) generation. By contrast, reduced ROS or Mapk14 deficiency downregulated PD-L1. Allogeneic offspring were born after SSC transplantation into congenitally infertile and chemically castrated mice. Thus, SSCs have unique immunological properties, which make allogeneic recipients into "surrogate fathers."
睾丸是一个免疫特权器官。人们认为睾丸体细胞微环境负责免疫抑制。然而，精原干细胞（SSC）的免疫学特性仍然未知。在这里，我们通过增强 SSCs 中免疫抑制性 PD-L1 的表达来报告同基因后代的诞生。体外补充 GDNF 和 FGF2 可增加 SSCs 中 PD-L1 的表达。培养的 SSCs 维持了 >1 年的同种异体精子发生。然而，SSC 中 Pd-l1 家族基因的耗竭或基因编辑阻止了同种异体精子发生，这表明生殖细胞负责抑制同种异体反应。PD-L1 是由 MAPK14-BCL6B 途径的激活诱导的，该途径通过产生活性氧（ROS）来驱动自我更新。相比之下，减少 ROS 或 Mapk14 缺乏会下调 PD-L1。SSC 移植到先天性不育和化学去势的小鼠后，可产生同基因后代。因此，SSC 具有独特的免疫学特性，使同种异体受者成为“代孕父亲”。
