Abstract
Recent studies have reported that the immune system significantly mediates skeletal muscle repair and regeneration. Additionally, biological scaffolds have been shown to play a role in polarizing the immune microenvironment toward pro-myogenic outcomes. Moreover, myostatin inhibitors are known to promote muscle regeneration and ameliorate fibrosis in animal models of Duchenne muscular dystrophy (DMD), a human disease characterized by chronic muscle degeneration. Biological scaffolds and myostatin inhibition can potentially influence immune-mediated regeneration in the dystrophic environment, but have not been evaluated together. Toward this end, here we created an injectable biological scaffold composed of hyaluronic acid and processed skeletal muscle extracellular matrix. This material formed a cytocompatible hydrogel at physiological temperatures in vitro When injected subfascially above the tibialis anterior muscles of both WT and dystrophic mdx-5Cv mice, a murine model of DMD, the hydrogel spreads across the entire muscle before completely degrading at 3 weeks in vivo We found that the hydrogel is associated with CD206+ pro-regenerative macrophage polarization and elevated anti-inflammatory cytokine expression in both WT and dystrophic mice. Co-injection of both hydrogel and myostatin inhibitor significantly increased FoxP3+ regulatory T cell modulation and Foxp3 gene expression in the scaffold immune microenvironment. Finally, delivery of myostatin inhibitor with the hydrogel increased its bioactivity in vivo, and transplantation of immortalized human myoblasts with the hydrogel promoted their survival in vivo This study identifies a key role for biological scaffolds and myostatin inhibitors in modulating a pro-regenerative immune microenvironment in dystrophic muscle.
Highlights
Recent studies have reported that the immune system significantly mediates skeletal muscle repair and regeneration
Hyaluronic acid (HA) was chemically modified with N-hydroxysuccinimide (NHS) to form HA-NHS, which was combined with processed skeletal muscle ECM tissue (M-ECM) at a 1:3 ratio (HA/ECM) to yield 6% (w/v) HA-NHS/M-ECM composite biological hydrogels
As depicted in a set of sequential time-lapse images using a sample of material labeled with blue dye, the hydrogel is capable of spreading throughout an entire tibialis anterior (TA) muscle with a single subfascial injection, as evidenced by visualization of the dye-labeled hydrogel spreading across the entire TA (Fig. 1B)
Summary
Recent studies have reported that the immune system significantly mediates skeletal muscle repair and regeneration. Biological scaffolds and myostatin inhibition can potentially influence immune-mediated regeneration in the dystrophic environment, but have not been evaluated together Toward this end, here we created an injectable biological scaffold composed of hyaluronic acid and processed skeletal muscle extracellular matrix. We found that the hydrogel is associated with CD206؉ pro-regenerative macrophage polarization and elevated anti-inflammatory cytokine expression in both WT and dystrophic mice Coinjection of both hydrogel and myostatin inhibitor significantly increased FoxP3؉ regulatory T cell modulation and Foxp gene expression in the scaffold immune microenvironment. Biological scaffold promotes regenerative response in mdx antibody RK35 has demonstrated the capacity to increase muscle mass in both mice and cynomolgus monkeys, and a humanized version (domagrozumab) has been previously evaluated in clinical trials for the treatment of DMD [17,18,19,20]
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