Stem Cell Research & Therapy (Feb 2018)

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

DOI
https://doi.org/10.1186/s13287-018-0788-2
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 15

Abstract

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Abstract 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 × 105 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.

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