Embryonic stem cell-derived cardiomyocytes for the treatment of doxorubicin-induced cardiomyopathy

Danúbia, Silva Dos Santos, Guilherme Visconde, Brasil, Isalira Peroba Rezende, Ramos, Fernanda Cristina Paccola, Mesquita, Tais Hanae, Kasai-Brunswick, Michelle Lopes Araújo, Christie, Gustavo Monnerat, Cahli, Raiana Andrade Quintanilha, Barbosa, Sandro Torrentes, Da Cunha, Jonathas Xavier, Pereira, Emiliano, Medei, Antonio Carlos, Campos De Carvalho, Adriana Bastos, Carvalho, Regina Coeli Dos Santos, Goldenberg

Stem Cell Research and Therapy | 2018

© 2018 The Author(s). Background: Doxorubicin (Dox) is a chemotherapy drug with limited application due to cardiotoxicity that may progress to heart failure. This study aims to evaluate the role of cardiomyocytes derived from mouse embryonic stem cells (CM-mESCs) in the treatment of Dox-induced cardiomyopathy (DIC) in mice. Methods: The mouse embryonic stem cell (mESC) line E14TG2A was characterized by karyotype analysis, gene expression using RT-PCR and immunofluorescence. Cells were transduced with luciferase 2 and submitted to cardiac differentiation. Total conditioned medium (TCM) from the CM-mESCs was collected for proteomic analysis. To establish DIC in CD1 mice, Dox (7.5 mg/kg) was administered once a week for 3 weeks, resulting in a cumulative Dox dose of 22.5 mg/kg. At the fourth week, a group of animals was injected intramyocardially with CM-mESCs (8 × 10 5 cells). Cells were tracked by a bioluminescence assay, and the body weight, echocardiogram, electrocardiogram and number of apoptotic cardiomyocytes were evaluated. Results: mESCs exhibited a normal karyotype and expressed pluripotent markers. Proteomic analysis of TCM showed proteins related to the negative regulation of cell death. CM-mESCs presented ventricular action potential characteristics. Mice that received Dox developed heart failure and showed significant differences in body weight, ejection fraction (EF), end-systolic volume (ESV), stroke volume (SV), heart rate and QT and corrected QT (QTc) intervals when compared to the control group. After cell or placebo injection, the Dox + CM-mESC group showed significant increases in EF and SV when compared to the Dox + placebo group. Reduction in ESV and QT and QTc intervals in Dox + CM-mESC-treated mice was observed at 5 or 30 days after cell treatment. Cells were detected up to 11 days after injection. The Dox + CM-mESC group showed a significant reduction in the percentage of apoptotic cardiomyocytes in the hearts of mice when compared to the Dox + placebo group. Conclusions: CM-mESC transplantation improves cardiac function in mice with DIC.