Designed Minibinders Rewire Receptor Signaling to Enable Functional Human Myogenic Reprogramming
Authors: Riya Keshri, Zachary Foreman, Phillip Barrett, Alexander Robinson, Gabriela Reyes, Ashish Phal, Aditya Krishna Kumar, Ethan Narog, Melodie Chiu, Shruti Jain, Xinru Wang, David Lee, Marc Exposit, Mohamad Adedi, Alec ST Smith, Sanjay Srivatsan, Jay Shendure, Julie Mathieu, David L Mack, David Baker, Hannele Ruohola-Baker
Originally Published in: BioRxiv (April 2026) (Download)
Abstract
Sarcopenia, loss of muscle mass is a considerable health burden that demands immediate societal attention. Direct myogenic somatic cell reprogramming, a potential muscle regeneration method is constrained by an inability to control the signaling logic that governs cell fate. Here, we show that this barrier can be overcome using AI-designed receptor modulators. Screening de novo minibinders, we identify a synthetic protein cocktail, C6-DPC, that drives efficient human fibroblast-to-muscle transdifferentiation with robust structural and metabolic maturation. C6-DPC reprograms extracellular signaling by activating pro-myogenic FGFR1/2c pathways while suppressing anti-myogenic inputs through ALK1 and TGFBR2; targeted depletion of ALK1 is sufficient to lower the reprogramming barrier. Inflammatory signaling via gp130 emerges as a dominant checkpoint, and its inhibition further enhances conversion. Engineered tissues generate high twitch and tetanic forces in both wild-type and dystrophin-deficient human cells. These findings demonstrate that programmable synthetic ligands can rewrite receptor-level signaling to direct cell fate and enable functional tissue regeneration.
