Journal article
RNA innate immunity constitutes a barrier for interspecies chimerism
Cell, Vol.189(1), pp.23-33.e16
01/08/2026
DOI: 10.1016/j.cell.2025.10.039
PMCID: PMC13008183
PMID: 41289993
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.
[Display omitted]
•Co-culture with human PSCs triggers the RNA innate immune response in mouse PSCs•Mavs knockout weakens the mouse PSCs’ competitiveness and improves human PSC survival•Mavs-deficient mouse embryos boost human PSC survival and chimerism in vivo•Interspecies PSC co-culture enables direct, contact-dependent horizontal RNA transfer
Interspecies PSC co-culture induces horizontal RNA transfer that activates innate immunity in “winner” mouse cells, a response that is alleviated by Mavs deletion, thereby enhancing “loser” human PSC survival and chimerism.
Details
- Title: Subtitle
- RNA innate immunity constitutes a barrier for interspecies chimerism
- Creators
- Yingying Hu - The University of Texas Southwestern Medical CenterHai-Xi Sun - BGI ResearchMasahiro Sakurai - The University of Texas Southwestern Medical CenterZhou Luo - The University of Texas Southwestern Medical CenterAmanda E. Jones - The University of Texas Southwestern Medical CenterTianlei Cheng - The University of Texas Southwestern Medical CenterJia Huang - The University of Texas Southwestern Medical CenterLizhong Liu - The University of Texas Southwestern Medical CenterCanbin Zheng - The University of Texas Southwestern Medical CenterJie Li - University of Chinese Academy of SciencesYue Lu - The University of Texas Southwestern Medical CenterBenjamin Ravaux - The University of Texas Southwestern Medical CenterBingbing He - The University of Texas Southwestern Medical CenterYi Ding - The University of Texas Southwestern Medical CenterTianbin Liu - BGI Group (China)Yan Wu - University of Chinese Academy of SciencesZhijian J. Chen - The University of Texas Southwestern Medical CenterJohn M. Abrams - The University of Texas Southwestern Medical CenterElizabeth H. Chen - The University of Texas Southwestern Medical CenterYing Gu - BGI Group (China)Jun Wu - Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.189(1), pp.23-33.e16
- DOI
- 10.1016/j.cell.2025.10.039
- PMID
- 41289993
- PMCID
- PMC13008183
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 01/08/2026
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9985150205902771
Metrics
1 Record Views