Dr. John Ngo

Synthetic Mechanobiology: probing and programming how cells sense and transmit force-based cues

ABSTRACT:

Cells interpret mechanical stimuli from their environments and neighbors, but the ability to engineer customized mechanosensing capabilities has remained a synthetic and mechanobiology challenge. Here we introduce tension-tuned synthetic Notch (SynNotch) receptors to convert extracellular and intercellular forces into specifiable gene expression changes. By elevating the tension requirements of SynNotch activation, in combination with structure-guided mutagenesis, we designed a set of receptors with mechanical sensitivities spanning the physiologically relevant picoNewton range. Cells expressing these receptors can distinguish between varying tensile forces and respond by enacting customizable transcriptional programs. We applied these tools to design a decision-making circuit, through which fibroblasts differentiate into myoblasts upon stimulation with distinct tension magnitudes. We also characterize cell-generated forces transmitted between cells during Notch signaling and we describe a new strategy for gauging the unbinding forces of ECM-bound proteins. Overall, this work provides insight into how mechanically induced changes in protein structure can be used to transduce physical forces into biochemical signals. The system should facilitate the further programming and dissection of force-related phenomena in biological systems.