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Stem Cell Res Ther. 2018 Feb 5;9(1):30. doi: 10.1186/s13287-018-0788-2.

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

Author information

1
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho 373 Bloco G-Sala G2-053, Rio de Janeiro, RJ, 21941-902, Brazil.
2
Centro Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Bloco M, Rio de Janeiro, RJ, 21941-902, Brazil.
3
Departamento de Patologia-Faculdade de Medicina, Hospital Universitário Clementino Fraga Filho, Universiade Federal do Rio de Janeiro, Av. Rodolpho Paulo Rocco, 255, Sub-solo, SAP, Rio de Janeiro, RJ, 21910-590, Brazil.
4
Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Av. Carlos Chagas Filho 373, Rio de Janeiro, RJ, 21941-902, Brazil.
5
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho 373 Bloco G-Sala G2-053, Rio de Janeiro, RJ, 21941-902, Brazil. rcoeli@biof.ufrj.br.
6
Centro Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Bloco M, Rio de Janeiro, RJ, 21941-902, Brazil. rcoeli@biof.ufrj.br.
7
Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Av. Carlos Chagas Filho 373, Rio de Janeiro, RJ, 21941-902, Brazil. rcoeli@biof.ufrj.br.

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.

KEYWORDS:

Cardiomyocytes derived from mouse embryonic stem cells; Cell therapy; Dox-induced cardiomyopathy; Heart failure

PMID:
29402309
PMCID:
PMC5799903
DOI:
10.1186/s13287-018-0788-2
[Indexed for MEDLINE]
Free PMC Article

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