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.
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.
Stem Cell Res Ther. 2018 Feb 5;9(1):30. doi: 10.1186/s13287-018-0788-2.
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.
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 cells). Cells were tracked by a bioluminescence assay, and the body weight, echocardiogram, electrocardiogram and number of apoptotic cardiomyocytes were evaluated.
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.
CM-mESC transplantation improves cardiac function in mice with DIC.
多柔比星（Dox）是一种化疗药物，由于可能发展为心力衰竭的心脏毒性，其应用受到限制。本研究旨在评估来源于小鼠胚胎干细胞（CM-mESCs）的心肌细胞在治疗小鼠多柔比星诱导的心肌病（DIC）中的作用。
通过核型分析、RT-PCR 和免疫荧光对小鼠胚胎干细胞（mESC）系 E14TG2A 进行鉴定。用荧光素酶 2 转导细胞，并进行心脏分化。收集 CM-mESCs 的总条件培养基（TCM）进行蛋白质组学分析。为了在 CD1 小鼠中建立 DIC，每周给予多柔比星（7.5mg/kg）一次，共 3 周，累积多柔比星剂量为 22.5mg/kg。在第 4 周，一组动物经心肌内注射 CM-mESCs（8×10^5 个细胞）。通过生物发光测定法追踪细胞，评估体重、超声心动图、心电图和凋亡心肌细胞数量。
mESCs 具有正常核型，并表达多能标志物。TCM 的蛋白质组学分析显示与细胞死亡负调控相关的蛋白。CM-mESCs 呈现心室动作电位特征。接受多柔比星的小鼠发生心力衰竭，与对照组相比，体重、射血分数（EF）、收缩末期容积（ESV）、每搏输出量（SV）、心率和 QT 及校正 QT（QTc）间期有显著差异。与多柔比星+安慰剂组相比，多柔比星+CM-mESC 组在细胞或安慰剂注射后 EF 和 SV 显著增加。在细胞治疗后 5 或 30 天，观察到多柔比星+CM-mESC 治疗组 ESV 和 QT 及 QTc 间隔缩短。注射后 11 天仍可检测到细胞。与多柔比星+安慰剂组相比，多柔比星+CM-mESC 组小鼠心脏中的凋亡心肌细胞百分比显著降低。
CM-mESC 移植可改善 DIC 小鼠的心脏功能。
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