Young cardiac telocyte-derived exosomes rejuvenate aging hearts in rats

Effective clinical strategies for rejuvenating aging hearts are needed to reverse and cure aging-related pathological cardiac degeneration. The present study was designed to investigate the potential rejuvenating effects of young cardiac telocyte (CT)-derived exosomes (Y-CT-exos) on cardiac aging and aging-related pathological cardiac degeneration.

Y-CT-exos were prepared from young CTs. Twenty-four-month-old female Sprague‒Dawley rats were used as an aged model to evaluate the benefits of Y-CT-exos on cardiac aging and aging-related pathological cardiac degeneration. Nanoparticle tracking analysis, zeta potential measurements, Western blotting, qPCR, β-gal, ROS and PKH26 staining, multiplex immunoassays, Masson's trichrome and immunohistochemical staining, motor function tests, wheat germ agglutinin staining and echocardiography, etc., were performed to evaluate the quality and distribution of the Y-CT-exos and their effects against cardiac aging. RNA sequencing was performed to compare the changes in the transcriptomes between aged hearts and Y-CT-exos-treated aged hearts, and differentially expressed genes (DEGs) were identified. Ingenuity pathway analysis (IPA) was used to identify related genes, their associated pathways, and the up- and downstream interaction networks underlying the rejuvenating effects of Y-CT-exos on cardiac aging and cardiac pathological improvement.

Y-CT-exos rejuvenated cardiac aging by ameliorating the senescence of cardiomyocytes and cardiac fibroblasts, the accumulation of DNA and ROS damage in cardiomyocytes, inflammation in the hearts and body of aged rats, promoting the proliferation of cardiomyocytes, improving aging-related decreases in cardiac function, and alleviating cardiomyocyte hypertrophy and cardiac fibrosis. In addition, the related genes, their associated pathways and the up- and downstream interaction networks underlying the therapeutic effects of reversed cellular senescence (inhibition of the p38 MAPK signaling pathway and activation of the antioxidant function of vitamin C), inflammatory aging (inhibition of the inflammasome pathway), and cardiomyocyte hypertrophy, were revealed.

Y-CT-exos, the identified genes and their up- and downstream interaction networks, which are involved in the alleviation of cellular senescence, inflammatory aging and cardiomyocyte hypertrophy, have great potential for the development of novel cell-free therapies to rejuvenate aging hearts and ameliorate the aging-related decrease in cardiac function, cardiac hypertrophy and cardiac fibrosis.