Mechanically Engineered MSCs Ameliorate Muscle Fibrosis and Improve Muscle Functional Recovery in Duchenne Muscular Dystrophy

Muscle fibrosis is a chronic condition for which no fully effective therapeutic treatment is currently available. The disease impairs muscle architecture and functionality, significantly impacting the patient’s quality of life. The hallmark of muscle fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins, particularly fibronectin and collagen. Fibronectin deposition is thought to be an early event is disease development and may contribute to the initiation of the fibrotic process. In this study, we engineered mesenchymal stromal cells (MSCs) using an alginate hydrogel system to enhance their production of matrix metalloproteinases (MMPs) and subsequently evaluated the therapeutic potential of this enhanced matrix-remodeling strategy in a rodent model of muscle fibrosis. Our data suggest that culturing MSCs within a softer hydrogel (Young’s Modulus ~2 kPa) significantly enhances their production of MMP-2, 3, 9 and 10. Treatment with these enhanced matrix-remodeling enzymes significantly reduced fibronectin deposition and collagen accumulation in a rodent model of muscle fibrosis, supporting the therapeutic efficacy of our engineered approach. Furthermore, treated mice exhibited significantly improved locomotor performance, indicating that our engineered therapy not only mitigates pathological ECM accumulation but also facilitates functional muscle recovery.