RNA innate immunity constitutes a barrier for interspecies chimerism

Yingying Hu¹, Hai-Xi Sun², Masahiro Sakurai¹, Zhou Luo¹, Amanda E Jones³, Tianlei Cheng¹, Jia Huang¹, Lizhong Liu¹, Canbin Zheng¹, Jie Li², Yue Lu¹, Benjamin Ravaux¹, Bingbing He¹, Yi Ding¹, Tianbin Liu⁴, Yan Wu², Zhijian J Chen⁵, John M Abrams³, Elizabeth H Chen⁶, Ying Gu⁷, Jun Wu⁸

Affiliations

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Beijing 102601, China.
³ Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen 518083, China.
⁵ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Beijing 102601, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen 518083, China; BGI Cell, Shenzhen 518083, China. Electronic address: guying@genomics.cn.
⁸ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jun2.wu@utsouthwestern.edu.

PMID: 41289993
PMCID: PMC13008183 (available on 2026-11-24)
DOI: 10.1016/j.cell.2025.10.039

RNA innate immunity constitutes a barrier for interspecies chimerism

Yingying Hu et al. Cell. 2026.

. 2026 Jan 8;189(1):23-33.e16.

doi: 10.1016/j.cell.2025.10.039. Epub 2025 Nov 24.

Authors

Affiliations

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Beijing 102601, China.
³ Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen 518083, China.
⁵ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Beijing 102601, China; Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen 518083, China; BGI Cell, Shenzhen 518083, China. Electronic address: guying@genomics.cn.
⁸ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jun2.wu@utsouthwestern.edu.

PMID: 41289993
PMCID: PMC13008183 (available on 2026-11-24)
DOI: 10.1016/j.cell.2025.10.039

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.

Keywords: MAVS; RLR pathway; RNA innate immunity; cell competition; horizontal RNA transfer; human pluripotent stem cells; interspecies PSC co-culture; interspecies chimeras; mouse epiblast stem cells; tunneling nanotube.

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Conflict of interest statement

Declaration of interests Y.H., Y.G., and J.W. are inventors on a patent application (applied through the Board of Regents of The University of Texas System, PCT/US2024/018702) entitled “RNA sensing and innate immunity constitutes a barrier for interspecies chimerism” arising from this work.

Update of

RNA Sensing and Innate Immunity Constitutes a Barrier for Interspecies Chimerism.
Hu Y, Sun HX, Sakurai M, Jones AE, Liu L, Cheng T, Zheng C, Li J, Ravaux B, Luo Z, Ding Y, Liu T, Wu Y, Chen EH, Chen ZJ, Abrams JM, Gu Y, Wu J. Hu Y, et al. bioRxiv [Preprint]. 2023 Mar 9:2023.03.07.531624. doi: 10.1101/2023.03.07.531624. bioRxiv. 2023. Update in: Cell. 2026 Jan 8;189(1):23-33.e16. doi: 10.1016/j.cell.2025.10.039. PMID: 36945615 Free PMC article. Updated. Preprint.

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RNA innate immunity constitutes a barrier for interspecies chimerism

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RNA innate immunity constitutes a barrier for interspecies chimerism

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