Abstract
Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2–5-month-old mdx mice intravenously injected with 1 × 105 Wharton’s jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD.
Highlights
Skeletal muscle fibrosis, one of the typical symptoms of Duchenne muscular dystrophy (DMD), is an abnormal accumulation of extracellular matrix (ECM) components in muscle tissue and is observed in patients with the end-stage of DMD [1,2]
Skeletal muscle fibrosis and accumulation of calcium/necrotic fibers are increased in DMD mice [7,33,34,35]
As Wharton’s jelly (WJ)-Mesenchymal stem cells (MSCs) exert anti-apoptotic effects on skeletal muscle cells [27], we here investigated whether these cells could have anti-fibrotic effects, and sought to elucidate the main paracrine factor underlying such effects
Summary
One of the typical symptoms of Duchenne muscular dystrophy (DMD), is an abnormal accumulation of extracellular matrix (ECM) components in muscle tissue and is observed in patients with the end-stage of DMD [1,2]. Muscle function is impaired and the regeneration ability of skeletal muscle is diminished, which leads to muscle dysfunction [3,4,5]. This pathological symptom is considered a hallmark of muscular dystrophies. Various studies have investigated the mechanisms underlying skeletal muscle fibrosis and have identified several factors that affect fibrosis, such as oxidative stress, inflammation, and aging [1,6,7]. Alleviation of oxidative stress-induced fibrosis is important in relieving the pathologic condition in patients with DMD. There are several approaches to resolving fibrosis in patients with DMD, but no effective treatment has been developed to date [10]
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