Transcriptome-Optimized Hydrogel Design of a Stem Cell Niche for Enhanced Tendon Regeneration

This study introduces a transcriptome-guided materials design strategy to engineer hydrogels that better replicate the native tendon stem/progenitor cell (TSPC) niche. By integrating scRNA-seq datasets with bioinformatics and functional screening, the authors identified extracellular matrix cues and biophysical properties that promote TSPC tenogenic differentiation and improve functional tendon healing. Using this knowledge, they developed a composite hydrogel with optimized matrix stiffness, ligand presentation, and viscoelasticity that enhanced TSPC alignment, mechanosensitivity, and expression of tendon-related markers. In a preclinical Achilles tendon defect model, the optimized hydrogel significantly improved collagen organization, mechanical strength, and overall regenerative outcomes compared to conventional hydrogels. The work establishes a new paradigm for regenerative biomaterial design driven by cellular transcriptomic signatures.