Mechanical Signal-Tailored Hydrogel Microspheres Recruit and Train Stem Cells for Precise Differentiation.

The aberrant mechanical microenvironment in degenerated tissues induces misdirection of cell fate, making it challenging to achieve efficient endogenous regeneration. Herein, a hydrogel microsphere-based synthetic niche with integrated cell recruitment and targeted cell differentiation properties via mechanotransduction was constructed for enhanced endogenous regeneration. Through the incorporation of microfluidics and photo-polymerization strategies, we prepared fibronectin (Fn) modified methacrylated gelatin (GelMA) microspheres with the independently tunable elastic modulus(1-10Kpa) and ECM ligand density (2 and 10 μg/ml), allowing a wide range of cytoskeleton modulation to trigger the corresponding mechanobiological signaling to direct cell fate. The combination of the soft matrix (2Kpa) and low ligand density (2 μg/ml) could support the nucleus pulposus (NP)-like differentiation of intervertebral disc (IVD) progenitor/stem cells by translocating Yes-associated protein (YAP), without the addition of inducible biochemical factors. Meanwhile, platelet-derived growth factor-BB was loaded onto Fn-GelMA microspheres (PDGF@Fn-GelMA) via the heparin-binding domain of Fn and exhibited continuous release for over 28 days to initiate endogenous cell recruitment. In in vivo experiments, hydrogel microsphere-niche maintained the IVD structure and stimulated ECM synthesis, thereby enhancing the endogenous regeneration of NP. Overall, this synthetic niche with cell recruiting and mechanical training capabilities offered a promising novel strategy for endogenous tissue regeneration. This article is protected by copyright. All rights reserved.