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Designed Minibinders Rewire Receptor Signaling to Enable Functional Human Myogenic Reprogramming
Riya Keshri1,2, Zachary Foreman2,3, Phillip Barrett2
1Department of Biochemistry, University of Washington, Seattle, United States.
Biorxiv : the Preprint Server for Biology
|May 7, 2026
Summary
Scientists used AI to design synthetic proteins that reprogram human cells into muscle cells. This breakthrough offers a new way to regenerate muscle tissue and combat sarcopenia, a common age-related condition.
Area of Science:
- Biotechnology
- Regenerative Medicine
- Cell Biology
Background:
- Sarcopenia, the loss of muscle mass, presents a significant health challenge.
- Direct myogenic somatic cell reprogramming for muscle regeneration is limited by control over cell fate signaling.
- Existing methods lack precise control over the signaling pathways that dictate cell differentiation.
Purpose of the Study:
- To overcome limitations in controlling cell fate during myogenic reprogramming.
- To develop AI-designed synthetic ligands for precise receptor modulation.
- To enable functional muscle tissue regeneration through controlled cell transdifferentiation.
Main Methods:
- Screening de novo minibinders to identify effective protein cocktails.
- Utilizing AI-designed receptor modulators to control extracellular signaling.
- Investigating the roles of FGFR1/2c, ALK1, TGFBR2, and gp130 signaling pathways.
- Engineering functional muscle tissues from reprogrammed human cells.
Main Results:
- A synthetic protein cocktail, C6-DPC, was identified to drive efficient human fibroblast-to-muscle transdifferentiation.
- C6-DPC reprogrammed signaling by activating pro-myogenic and suppressing anti-myogenic pathways.
- Inhibition of inflammatory signaling via gp130 further enhanced cell conversion.
- Engineered tissues from reprogrammed cells demonstrated robust structural and metabolic maturation, generating significant contractile forces.
Conclusions:
- AI-designed programmable synthetic ligands can rewrite receptor-level signaling to direct cell fate.
- This approach enables functional muscle tissue regeneration, offering a potential therapeutic strategy for sarcopenia and muscle disorders.
- Precise control over cell signaling pathways is key to overcoming barriers in regenerative medicine.
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