4.6 Article

Involvement of miR-34c in high glucose-insulted mesenchymal stem cells leads to inefficient therapeutic effect on myocardial infarction

Journal

CELLULAR SIGNALLING
Volume 27, Issue 11, Pages 2241-2251

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2015.07.024

Keywords

Mesenchymal stem cells; Angiogenesis; High glucose; Stem cell factor; MiR-34c

Categories

Funding

  1. National Research Foundation of Korea - Korean Government (MEST), Republic of Korea [2010-0020261, 2011-0024852]
  2. Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI12C0199, HI13C1527]
  3. National Research Foundation of Korea [2011-0024852] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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High glucose-insulted bone marrow-derived mesenchymal stem cells (BMCs) showed impaired angiogenesis along with downregulation of stem cell factor (SCF). This study was designed to determine the involvement of microRNAs (miR), which are actively involved in the physiological function of stem cells. We observed that miR-34c was significantly induced by high glucose treatment and blunted tube formation of BMCs. Stem cell factor (SCF) was confirmed as a target of miR-34c by 3'-UTR promoter analysis and Western blot. SCF knockdown by siRNA induced Kriippel-like factor 4 (KLF4) and resulted in the blockade of angiogenesis of BMCs. Sequentially, KLF4 overexpression completely blocked tube formation through inducing PAI-1 (plasminogen activator inhibitor-1). To study the action of miR-34c in terms of the therapeutic potential of BMCs, myocardial infarction (MI) was induced by ligation of the coronary artery in nude mice, BMCs transfected with miR-control or miR-34c were injected into the infarcted myocardium 7 days later, and histological studies were performed 2 weeks later. Cardiac fibrosis was 1824 +/- 4.7% in the miR-34c-BMC group and 10.01 +/- 02% in the miR-control-BMC group (p < 0.05). Cardiac function and vessel density were decreased in the miR-34c-BMC group compared with the miR-con-BMC group. Particularly, miR-34c-BMCs failed to incorporate into vessels. Our results show that the angiogenic activity of BMCs is finely regulated by the miR-34c-SCF-KLF4 axis, which is a potent translational target for optimizing the therapeutic activity of autologous BMCs for cardiac repair. (C) 2015 Elsevier Inc. All rights reserved.

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