RNA innate immunity constitutes a barrier for interspecies chimerism

Area of Science:

• Stem cell biology
• Immunology
• Developmental biology

Background:

• Generating human-animal chimeras is crucial for disease modeling and organ generation.
• Poor integration of human pluripotent stem cells (hPSCs) into host embryos hinders chimera creation.
• Current strategies primarily focus on modifying hPSCs, neglecting host embryo factors.

Purpose of the Study:

• To investigate the role of host embryo immunity in limiting human pluripotent stem cell (hPSC) integration.
• To identify mechanisms underlying the competitive elimination of hPSCs in interspecies chimeras.
• To explore strategies for enhancing human chimerism by modulating host immunity.

Main Methods:

• Utilized an interspecies stem cell competition model.
• Investigated RNA innate immune pathways in host cells.
• Generated and analyzed mouse embryos lacking key RNA sensing genes (e.g., Mavs).
• Assessed hPSC survival and chimerism levels.

Main Results:

• Host mouse cells' RNA innate immunity actively eliminates hPSCs.
• Disrupting host RNA sensing pathways enhances hPSC competitiveness and viability.
• Mouse embryos deficient in Mavs exhibit significantly improved human cell survival and chimerism.
• Horizontal RNA transfer between cells appears to trigger immune responses.

Conclusions:

• Host RNA innate immunity is a critical barrier to human chimerism.
• Modulating host immune pathways, specifically RNA sensing, can substantially improve human cell integration.
• Targeting host immunity offers a novel strategy for advancing interspecies chimera research and applications.