Single-cell omics identifies inflammatory signaling as a trans-differentiation trigger in mouse embryos

Area of Science:

• Developmental Biology
• Cellular Reprogramming
• Immunology

Background:

• Trans-differentiation, a direct cell lineage conversion, is not fully understood, limiting its therapeutic potential.
• Identifying universal principles governing cell fate plasticity is crucial for advancing regenerative medicine and developmental biology.

Purpose of the Study:

• To explore universal principles of trans-differentiation.
• To characterize common features and molecular triggers across different cell fate conversion processes.
• To investigate the role of inflammatory signaling in developmental-stress-induced cell transitions.

Main Methods:

• Single-cell transcriptomic analysis of endothelial-to-hematopoietic transition (EHT), endothelial-to-mesenchymal transition, and epithelial-to-mesenchymal transition in mouse embryos.
• Application of scoring indexes for entropy, transcription factor expression, and transition signals.
• Multimodal profiling integrating transcriptomic and chromatin accessibility data.
• Fate-mapping analyses.

Main Results:

• Identified common features of transition states, including inflammatory signatures.
• Discovered a conserved role for interleukin-33 as a trigger for multiple fate conversions.
• Demonstrated that inflammatory signaling regulates hematopoietic specification via chromatin accessibility and transcriptional programs.
• Showed that endothelium-specific Spi1 acts as an inflammatory effector safeguarding EHT.

Conclusions:

• Common transition states and signals, particularly inflammatory pathways, underpin developmental-stress-induced cell fate conversions.
• Interleukin-33 and Spi1 are critical regulators in trans-differentiation processes like EHT.
• Single-cell omics provides powerful insights into the mechanisms of cell plasticity.