中国科学院大学生命科学学院顾颖研究组报道了RNA先天免疫是种间嵌合的屏障。该项研究成果发表在2025年11月24日出版的《细胞》上。

利用种间PSC竞争模型，研究小组发现“赢家”同主题细胞中的RNA先天免疫驱动了hPSCs的竞争消除。破坏RNA传感通路会降低motheme PSCs的竞争力和活力，而缺乏Mavs （RNA先天免疫的关键基因）的motheme胚胎会显著提高人类细胞的存活率和嵌合性。该研究团队还发现，依赖于接触的水平RNA转移可能是这种免疫激活的基础。总的来说，他们的研究揭示了RNA先天免疫在细胞竞争中的一个以前未被认识到的作用，并证明靶向宿主免疫途径代表了一种改善动物体内人类嵌合的有力方法。

据介绍，利用人类多能干细胞（hPSCs）创造种间嵌合体为模拟人类发育和生成供体器官提供了一种有前途的策略；然而，人类细胞整合不良仍然是一个主要障碍。大多数现有的改善人类嵌合的努力都集中在基因修饰供体造血干细胞上，而改变宿主胚胎在很大程度上仍未被探索。

附：英文原文

Title: RNA innate immunity constitutes a barrier for interspecies chimerism

Author: Yingying Hu, Hai-Xi Sun, Masahiro Sakurai, Zhou Luo, Amanda E. Jones, Tianlei Cheng, Jia Huang, Lizhong Liu, Canbin Zheng, Jie Li, Yue Lu, Benjamin Ravaux, Bingbing He, Yi Ding, Tianbin Liu, Yan Wu, Zhijian J. Chen, John M. Abrams, Elizabeth H. Chen, Ying Gu, Jun Wu

Issue&Volume: 2025-11-24

Abstract: Creating interspecies chimeras with human pluripotent stem cells (hPSCs) offers a promising strategy for modeling human development and generating donor organs; however, poor human cell integration remains a major barrier. Most existing efforts to improve human chimerism focus on genetically modifying donor hPSCs, while altering the host embryo remains largely unexplored. Using an interspecies PSC competition model, we discovered that RNA innate immunity in “winner” mouse cells drives the competitive elimination of hPSCs. Disrupting RNA-sensing pathways reduced the competitiveness and viability of mouse PSCs, and mouse embryos lacking Mavs—a key gene in RNA innate immunity—led to markedly improved human cell survival and chimerism. We also found that contact-dependent horizontal RNA transfer likely underlies this immune activation. Overall, our study uncovers a previously unrecognized role for RNA innate immunity in cell competition and demonstrates that targeting host immune pathways represents a powerful approach to improve human chimerism in animals.

DOI: 10.1016/j.cell.2025.10.039

Source: https://www.cell.com/cell/abstract/S0092-8674(25)01244-9