Cardiac progenitor cells activated by mitochondrial delivery of resveratrol enhance the survival of a doxorubicin-induced cardiomyopathy mouse model via the mitochondrial activation of a damaged myocardium

• Published in: Journal of controlled release Vol. 269; pp. 177 - 188
• Main Authors: Abe, Jiro, Yamada, Yuma, Takeda, Atsuhito, Harashima, Hideyoshi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.01.2018
• Subjects: Animals; Antibiotics, Antineoplastic; Cardiomyopathies - chemically induced; Cardiomyopathies - metabolism; Cardiomyopathies - therapy; Cell Line; Coculture Techniques; Disease Models, Animal; Doxorubicin; Doxorubicin-induced cardiomyopathy; Male; Mice, Inbred C57BL; MITO cell; MITO-porter; Mitochondria, Heart - metabolism; Mitochondrial delivery; Myocardium - cytology; Myocardium - metabolism; Resveratrol; Resveratrol - administration & dosage; Stem Cell Transplantation; Stem Cells; DOPE; ESRRa; RES; Doxorubicin-induced cardiomyopathy; cTnI; PGC1α; NBD-DOPE; COX 1; OXPHOS; SDHA; bFGF; NAD; MITO-porter; DDS; Mitochondrial delivery; LVFS; Resveratrol; CPC; AMPK; Sirt1; SM; CLSM; MITO cell; Stem-cell transplantation
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.11.024

It has been reported that transplanting native cells would lack efficiency without producing artificial cell-tissue, due to the exaggerated oxidative stress in doxorubicin-induced cardiomyopathy. We attempted to activate cardiac progenitor cells (CPCs) by delivering resveratrol to mitochondria using a mitochondrial drug delivery system (MITO-Porter system). We first evaluated the viability of H9c2 cells (a cardio myoblast cell line) after doxorubicin treatment, where H9c2 cells were co-cultured with or without the mitochondria activated CPCs (referred to herein as MITO cell). We next evaluated the survival rate of doxorubicin treated mice, with or without the injection of MITO cells into the myocardium. Finally, we examined the molecular mechanism of the cell therapy by detecting oxidative stress and the induction of apoptosis in addition to quantification of the mRNA and protein levels about oxidative phosphorylation (OXPHOS). The MITO cell transplanted mice lived significantly longer than the conventional CPC transplanted ones. Oxidative stress and massive cell death were both significantly reduced in the MITO cell transplanted hearts, in which the expression levels of OXPHOS protein and gene were also higher than the control group. In doxorubicin-induced cardiomyopathy, the transplantation of MITO cells, which possess activated mitochondria, is more efficient compared to conventional CPC transplantation. [Display omitted]