Bone marrow-derived mesenchymal stem cells overexpressing MiR-21 efficiently repair myocardial damage in rats.

Yan-Ling Zeng,Xue-Qiong Wu,Xiao-Feng Luo,Hao Zheng,Ping Chen,Jin-Hua Ren,Zhi-Zhe Chen,Min Xiao,Xiao-Hong Yuan,Qiu-Ru Chen,Zhe-Yao Lin,Jian-Da Hu,Ting Yang,Shao-Zhen Chen,Yong-Quan Chen

doi:10.18632/oncotarget.16254

Abstract

ObjectiveWe investigated the ability of bone marrow derived mesenchymal stem cells (BMSCs) overexpressing microRNA-21 (miR-21) to repair cardiac damage induced by anthracyclines in rats.MethodsSprague-Dawley (SD) rats of 2~3 weeks old were selected to isolate and culture BMSCs. A lentivirus harboring pLVX-miR-21 was generated and transfected into rat BMSCs. The rats were assigned into an untreated negative control group, and groups injected with adriamycin alone or with adriamycin followed by BMSCs, pLVX-BMSCs or pLVX-miR-21-BMSCs (n = 10 each). Proliferation and migration of cells were detected by cholecystokinin-8 (CCK- 8) and transwell. MiR-21 expression, mRNA expressions of B cell lymphoma 2 (Bcl2), BAX (BCL-2-associated X protein) and vascular endothelial growth factor (VEGF) were tested by qRT-PCR. Western blotting was applied to detect protein expressions of Bcl-2, Bax and VEGF.ResultsUsing CCK- 8 and transwell assays, we found that pLVX-miR-21-BMSCs, which overexpressed miR-21, exhibited greater proliferation and migration than untransfected BMSCs or pLVX-BMSCs. Ultrasonic cardiograms and immunohistochemical analysis demonstrated that among the five groups, the pLVX-miR-21-BMSC group exhibited the most improved heart function and enhanced angiogenesis. Moreover, the pLVX-miR-21-BMSC group showed enhanced expression of Bcl-2, VEGF and Cx43 and reduced expression of Bax, BNP and troponin T.ConclusionThese findings suggest miR-21 overexpression enhanced the proliferation, invasiveness and differentiation of BMSCs as well as expression of key factors (Bcl-2, VEGF and Bax) essential for repairing the cardiac damage induced by anthracyclines and restoring heart function.

Highlights

Anthracyclines are effective drugs against various hematologic diseases and malignancies [1]
Using CCK- 8 and transwell assays, we found that pLVX-miR21-bone marrow-derived mesenchymal stem cells (BMSCs), which overexpressed miR-21, exhibited greater proliferation and migration than untransfected BMSCs or pLVX-BMSCs
The pLVX-miR-21-BMSC group showed enhanced expression of B cell lymphoma 2 (Bcl-2), vascular endothelial growth factor (VEGF) and Cx43 and reduced expression of BCL2-associated X protein (Bax), BNP and troponin T. These findings suggest miR-21 overexpression enhanced the proliferation, invasiveness and differentiation of BMSCs as well as expression of key factors (Bcl-2, VEGF and Bax) essential for repairing the cardiac damage induced by anthracyclines and restoring heart function

Summary

Introduction

Anthracyclines are effective drugs against various hematologic diseases and malignancies [1] Their clinical use is restrained by the cumulative dose-dependent cardiotoxicity that can result in irreversible chronic cardiac injury and congestive heart failure [2, 3]. The bone marrow-derived mesenchymal stem cells (BMSCs) are the most common MSCs that are used therapeutically in www.impactjournals.com/oncotarget various diseases including myocardial injury because they are extractable, survive better after transplantation and show weak immunogenicity [8]. The BMSCs differentiate into cardiomyocytes and replace the apoptotic myocardium thereby improving the function of damaged hearts [9]. They are critical for immunomodulatory function, inflammatory response and epithelial function [10]. Several upregulated miRNAs were shown to regulate differentiation of BMSCs [12]

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