Wharton's Jelly-Derived Mesenchymal Stem Cells Reduce Fibrosis in a Mouse Model of Duchenne Muscular Dystrophy by Upregulating microRNA 499.

Sang Eon Park,Jong Wook Chang,Alee Choi,Gyu Ha Ryu,Soo-Young Oh,Hong Bae Jeon,Jang Bin Jeong,Jeehun Lee,Shin Ji Oh,Sun Jeong Kim,Hyeongseop Kim,Suk-Joo Choi

doi:10.3390/biomedicines9091089

Abstract

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3–5 months old) were administered five different doses of WJ-MSCs through their tail veins. A week after injection, grip strength measurements, creatine kinase (CK) assays, immunohistochemistry, and western blots were performed for comparison between healthy mice, mdx control mice, and WJ-MSC-injected mdx mice. WJ-MSCs exerted dose-dependent multisystem therapeutic effects in mdx mice, by decreasing CK, recovering normal behavior, regenerating muscle, and reducing apoptosis and fibrosis in skeletal muscle. We also confirmed that miR-499-5p is significantly downregulated in mdx mice, and that intravenous injection of WJ-MSCs enhanced its expression, leading to anti-fibrotic effects via targeting TGFβR 1 and 3. Thus, WJ-MSCs may represent novel allogeneic “off-the-shelf” cellular products for the treatment of DMD and possibly other muscle disorders.

Highlights

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder characterized by progressive loss of muscle mass and function [1]
The symptom-relieving effects of Wharton’s jelly-derived mesenchymal stem cells (WJ-mesenchymal stem cells (MSCs)) were examined by measuring the level of serum creatine kinase (CK), an indicator of muscle disease
The muscle-regenerating and anti-apoptotic effects of Wharton’s jelly-derived (WJ)-MSCs were observed through myosin heavy chain and annexin V staining, respectively, with significant effects after dose 3 and similar or slightly increased effects at higher doses (Figure 1d,f,g)

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder characterized by progressive loss of muscle mass and function [1]. 1/3500 live male births and is caused by mutations in the dystrophin gene that prevent its expression [2]. It is characterized by progressive skeletal and cardiac muscle weakness, with premature death usually occurring at approximately 20 years of age [3,4,5]. Most gene therapies that are being developed are single-targeted for dystrophin [8,9]

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