Encoded Cell-Material Interactions to Reroute Cytokine Signaling for Regenerative Medicine

Area of Science:

• Regenerative Engineering
• Materials Science
• Stem Cell Biology

Background:

• Current regenerative engineering strategies lack effective auto-regulated feedback mechanisms for cell sensing and response to microenvironmental changes.
• Designer materials have advanced, but controlling cellular responses to subtle environmental cues remains a challenge.

Purpose of the Study:

• To develop a novel material-cell platform (nMATRIX) for sensing endogenous soluble ligands and directing cellular responses.
• To engineer synthetic Notch (synNotch) receptors for detecting monomeric cytokines and enabling programmed gene circuits.
• To create self-regulating regenerative therapies by coupling native soluble cues to customized cellular responses.

Main Methods:

• Demonstrated activation of synthetic Notch (synNotch) by endogenous multimeric cytokines in solution.
• Developed nMATRIX, a co-engineered material-cell platform for detecting soluble ligands and routing them to gene circuits.
• Tuned nMATRIX to recognize interleukins IL-1β and IL-6 using synNotch receptors and biomaterials.

Main Results:

• Achieved up to a 24-fold dynamic range in synNotch activation by soluble cytokines.
• nMATRIX demonstrated over 68-fold dynamic range in sensing IL-1β and IL-6, converting inflammatory inputs into orthogonal outputs.
• Reprogrammed cell phenotypes and modulated macrophage surface marker expression by repurposing inflammatory signals into anti-inflammatory cues.

Conclusions:

• nMATRIX provides a flexible, materials-based approach for self-regulating regenerative therapies.
• The platform enables tunable sensitivity in coupling native soluble cues to customized cellular responses.
• This work reveals a new activation modality for synNotch and expands its sensing capabilities to monomeric cytokines.