Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs.

TLDR

Dystrophin deficiency in mdx mice and CXMD dogs permits tracking of engrafted cardiomyocytes, providing a model for studying cell fate in muscular dystrophy. The study aimed to determine whether isolated fetal canine cardiomyocytes could form stable intracardiac grafts in adult CXMD dogs. Fetal canine cardiomyocytes were isolated, dissociated, and injected into the hearts of adult CXMD dogs. Stable fetal cardiomyocyte grafts persisted for at least 10 weeks in CXMD dogs, displayed mature intercalated discs and connexin43 gap junctions at donor‑host borders, did not provoke arrhythmias, and increased cardiomyocyte numbers.

Abstract

This report documents the formation of stable fetal cardiomyocyte grafts in the myocardium of dystrophic dogs. Preliminary experiments established that the dystrophin gene product could be used to follow the fate of engrafted cardiomyocytes in dystrophic mdx mice. Importantly, ultrastructural analyses revealed the presence of intercalated discs consisting of fascia adherens, desmosomes, and gap junctions at the donor-host cardiomyocyte border. To determine if isolated cardiomyocytes could form stable intracardiac grafts in a larger species, preparations of dissociated fetal canine cardiomyocytes were delivered into the hearts of adult CXMD (canine X-linked muscular dystrophy) dogs. CXMD dogs, like Duchenne muscular dystrophy patients and mdx mice, fail to express dystrophin in both cardiac and skeletal muscle. Engrafted fetal cardiomyocytes, identified by virtue of dystrophin immunoreactivity, were observed to be tightly juxtaposed with host cardiomyocytes as long as 10 wk after engraftment, the latest date analyzed. Confocal laser scanning microscopy revealed the presence of connexin43, a major constituent of the gap junction, at the donor-host cardiomyocyte border. The presence of intracardiac grafts was not associated with arrhythmogenesis in the CXMD model. These results indicate that fetal cardiomyocyte grafting can successfully augment cardiomyocyte number in larger animals.