Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice
Russell G. Rogers, … , Michael I. Lewis, Eduardo Marbán
Russell G. Rogers, … , Michael I. Lewis, Eduardo Marbán
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e125754. https://doi.org/10.1172/jci.insight.125754.
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Categories: Research Article Muscle biology Stem cells

Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice

Abstract

Dystrophin deficiency leads to progressive muscle degeneration in Duchenne muscular dystrophy (DMD) patients. No known cure exists, and standard care relies on the use of antiinflammatory steroids, which are associated with side effects that complicate long-term use. Here, we report that a single intravenous dose of clinical-stage cardiac stromal cells, called cardiosphere-derived cells (CDCs), improves the dystrophic phenotype in mdx mice. CDCs augment cardiac and skeletal muscle function, partially reverse established heart damage, and boost the regenerative capacity of skeletal muscle. We further demonstrate that CDCs work by secreting exosomes, which normalize gene expression at the transcriptome level, and alter cell signaling and biological processes in mdx hearts and skeletal muscle. The work reported here motivated the ongoing HOPE-2 clinical trial of systemic CDC delivery to DMD patients, and identifies exosomes as next-generation cell-free therapeutic candidates for DMD.

Authors

Russell G. Rogers, Mario Fournier, Lizbeth Sanchez, Ahmed G. Ibrahim, Mark A. Aminzadeh, Michael I. Lewis, Eduardo Marbán

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Figure 1

Cardiorespiratory benefits of systemic CDC or EXO delivery.

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Cardiorespiratory benefits of systemic CDC or EXO delivery. (A) Schemati...
(A) Schematic of the experimental design. Mice underwent baseline testing of exercise capacity and cardiac function, and then were injected with vehicle control (Dulbecco’s PBS; 100 μl), cardiosphere-derived cells (CDCs; 2.5 × 105 cells per 100 μl), or CDC-derived exosomes (EXOs; 2.0 × 109 particles per 100 μl) into the femoral vein. Animals were reassessed for exercise capacity and cardiac function 3 weeks later. (B and C) Exercise capacity, as determined by a graded exercise test, was significantly improved in CDC- and EXO-treated mdx mice after 3 weeks (n = 8–10 per group; WT n = 9). This effect was maintained for at least 6 weeks following CDC treatment (n = 5). (D) Representative echocardiogram tracings. Cardiac function, as measured by transthoracic echocardiography, was significantly improved in CDC- and EXO-treated mdx mice after 3 weeks (n = 7–8 per group; WT n = 7). (E) Pooled data from F reveal less interstitial fibrosis in CDC- and EXO-treated mdx hearts (n = 5 per group). (F) Representative Masson’s trichrome–stained micrographs from vehicle-treated, CDC-treated, and EXO-treated mdx hearts. Scale bars: 100 μm. Bar graphs depict mean ± SEM. Statistical significance was determined by ANOVA with P ≤ 0.05. When appropriate, a Newman-Keuls correction for multiple comparisons was applied. *Significantly different from baseline; #significantly different from vehicle. Dashed line represents mean of WT values.