Non-invasive regeneration therapy of dilated cardiomyopathy using G-CSF

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In UM-X7.1 strain hamsters, a model of human dilated cardiomyopathy, heart failure progressively develops and a half of them die by 30 weeks old. We ultrastructurally found typical autophagic vacuoles including degraded mitochondria, glycogen granules, and myelin-like figures and overexpressed ubiquitin, cathepsin D and Rab7 in many cardiomyocytes of this model. Importantly, most cardiomyocytes with leaky plasma membrane were positive for cathepsin D, suggesting a direct linkage between autophagic degeneration and cell death. Meanwhile, cardiomyocyte apoptosis appeared insignificant. Injection of granulocyte colony-stimulating factor (10 μg/kg/day) 5 days/week for 15 weeks, started at 15 weeks of age, improved survival among 30-week-old hamsters (100% vs. 53% in the untreated hamsters, p<0.0001), ventricular function and remodeling, increased cardiomyocyte size, and reduced myocardial fibrosis, followed by a dramatic reduction in the autophagic findings. It also resulted in downregulation of tumor necrosis factor-α and increase in activities of Akt, signal transducer and activator of transcription-3, and matrix metalloproteinases. However, there was no clear evidence of transdifferentiation from bone marrow cells into cardiomyocytes. In conclusion, autophagic death is important for cardiomyocyte loss in the cardiomyopathic hamster and granulocyte colony-stimulating factor has the beneficial effect mainly via antiautophagic mechanism rather than antiapoptosis or regeneration.