Synthetic signal propagation through direct cell-cell interaction

Area of Science:

• Cellular biology
• Systems biology
• Biophysics

Background:

• Contact-dependent cell communication is crucial for generating complex patterns in vivo.
• The Delta-Notch signaling pathway, involving ligand Delta and receptor Notch, mediates cell-cell interactions.
• Positive feedback loops are essential for signal amplification and pattern formation in biological systems.

Purpose of the Study:

• To engineer a cell-cell positive feedback loop using the Delta-Notch system in cultured mammalian cells.
• To investigate the ability of this engineered system to generate propagating signals and bistability.
• To demonstrate the sufficiency of positive feedback for creating discrete cell populations with distinct signaling states.

Main Methods:

• Utilized the Delta-Notch signaling system with engineered transcriptional cascades.
• Incorporated Lunatic fringe as a positive regulator to amplify Notch responses.
• Employed mathematical modeling to determine optimal amplification levels for signal propagation.
• Observed signal propagation and bistability in cultured cell populations.

Main Results:

• Successfully constructed a cell-cell positive feedback loop amplifying Delta-Notch signaling.
• Achieved propagation of the Delta signal between adjacent cells.
• Generated bistability, resulting in discrete cell populations that were either Delta-positive or Delta-negative.
• Demonstrated that the positive feedback loop is sufficient for signal propagation and population-level bistability.

Conclusions:

• The engineered Delta-Notch positive feedback loop effectively generates signal propagation and cell population-level bistability.
• This study provides a foundation for engineering more complex cellular patterns in mammalian systems.
• Contact-dependent cell communication, when engineered with positive feedback, can control cell fate and organization.