Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by loss of motor neurons and degeneration of neuromuscular junctions. To improve disease progression, previous studies have suggested many options that have shown beneficial effects in diseases, especially stem cell therapy. In this study, we used repeated intramuscular transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) and observed positive effects on muscle atrophy and oxidative stress. In an in vivo study, motor function, body weight and survival rate were assessed, and skeletal muscle tissues were analyzed by western blotting and immunohistochemistry. After intramuscular transplantation, the hUCB-MSCs survived within the skeletal muscle for at least 1 week. Transplantation ameliorated muscle atrophy and the rate of neuromuscular degeneration in skeletal muscle through reductions in intracellular ROS levels. Both expression of skeletal muscle atrophy markers, muscle atrophy F-box (MAFbx)/atrogin1 and muscle RING finger 1 (MuRF1), were also reduced; however, the reductions were not significant. Moreover, transplantation of hUCB-MSCs improved protein synthesis and inhibited the iNOS/NO signaling pathway through AMPK activation. Our results suggest that repeated intramuscular transplantation of hUCB-MSCs can be a practical option for stem cell therapy for ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by loss of motor neurons and degeneration of neuromuscular junctions
We found that TGF-β1 treatment increased the number of low width C2C12 cell myotubes compared to control group (0–10 μm; TGF-β1: 8.14, Control: 5.13, 10–15 μm TGF-β1: 23.0, Control: 16.3) and hUCB-MSCs group ameliorated decrease of the number of high width C2C12 cell myotubes compared to the TGF-β1 treated group (P < 0.05, 15–20 μm TGF-β1: 6.14, hUCB-MSCs: 11.7, 20–30 μm TGF-β1: 2.71, hUCB-MSCs: 8.00)
This study showed that repeated transplantation of hUCB-MSCs into the gastrocnemius muscles of hSOD1-G93A mice can be a therapeutic strategy to alleviate disease progression
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by loss of motor neurons and degeneration of neuromuscular junctions. Previous studies have suggested many options that have shown beneficial effects in diseases, especially stem cell therapy. We used repeated intramuscular transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) and observed positive effects on muscle atrophy and oxidative stress. Samuel and colleagues provided evidence that AMPK activation alleviates synaptic dysfunction of the outer retina in aged mice through synaptic remodeling[18,19] Overall, it is unclear whether activation of AMPK signaling is harmful or beneficial in ALS, previous studies have suggested that AMPK signaling is an important molecular target for therapeutic strategies for ALS. In recent clinical trials, intrathecal and intramuscular administration of human mesenchymal stem cells (hMSCs) in patients with ALS were found to be safe and to provide beneficial effects for patients, including up to 25% improvement in the slope of progression. Application of hMSCs could lead to the generation of beneficial effects for neurodegenerative diseases
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