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Intravenous Delivery of Cardiosphere‐Derived Cells Improves Striated Muscle Function and Structure in a Murine Model of Duchenne Muscular Dystrophy
Author(s) -
Rogers Russell G,
Aminzadeh Mark A,
Fournier Mario,
Gouin Kenneth,
Sanchez Lizbeth,
Li Liang,
Sakoda Chris,
Marban Eduardo
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.877.10
Subject(s) - duchenne muscular dystrophy , medicine , dystrophin , skeletal muscle , cardiomyopathy , mdx mouse , cardiac function curve , ejection fraction , dilated cardiomyopathy , cardiology , myocyte , muscular dystrophy , heart failure
Duchenne muscular dystrophy (DMD), the most common inherited muscular disease, affects approximately 1 in 3,500 live‐born males worldwide. Loss of dystrophin results in a myriad of dysfunctional cellular processes that ultimately manifest as severe and progressive muscle‐wasting in both cardiac and skeletal muscle. DMD patients are clinically characterized by an early loss of ambulation followed by dilated cardiomyopathy in the second decade of life. There is no cure for DMD and current treatments marginally slow the progression of the disease course. Cardiosphere‐derived cells (CDCs) are cardiac progenitor/stromal cells with regenerative, angiogenic, anti‐inflammatory, and anti‐fibrotic properties. Previous research has demonstrated that CDCs are efficacious in treating both ischemic and non‐ischemic heart disease, including Duchenne cardiomyopathy in mdx mice – a mouse model of DMD. The latter work motivated the ongoing HOPE‐Duchenne clinical trial to treat DMD‐associated cardiomyopathy. Here, we sought to explore the potential of CDCs to treat both cardiac and skeletal myopathies when delivered systemically. A single bolus of syngeneic CDCs or vehicle were administered via the femoral vein of 10‐month‐old mdx mice. Baseline and three week follow up measurements of ambulatory capacity, in vivo cardiac function, and isolated skeletal muscle function were recorded. Systemic delivery of CDCs partially reversed the dystrophic phenotype in the heart and skeletal muscle of mdx mice. Specifically, CDC treated mice ran 34.6% (p = 0.01) farther than vehicle‐treated mice. Moreover, CDC treatment improved cardiac ejection fraction by 18.7% (p = 0.008) and isometric force developed by the soleus muscle by 47.8% (p < 0.001), to levels comparable to those in age‐matched wild type controls. Histological examination of the hearts and solei revealed fewer necrotic lesions in CDC treated mice. Interestingly, solei from CDC treated mice contained more centrally nucleated myofibers (208.7 ± 20.7 vs 106.8 ± 9.0, p = 0.004), consistent with enhanced active regeneration. Further, immunohistological staining of the soleus demonstrated that CDC treatment promoted nascent myotube formation, indicating replenishment of a pool of fusion‐competent myoblasts. These data demonstrate that a single intravenous infusion of syngeneic CDCs is sufficient to impact favorably on the phenotype of the mdx mouse. Given that CDCs are already in advanced clinical testing, the present work motivates clinical testing of CDCs delivered systemically to DMD patients, looking for improvements in cardiac and skeletal muscle function and biomarkers. Support or Funding Information NIH T32 HL116273