Hypoxia-Inducible Factor 1 Alpha Contributes to Cardiac Healing in Mesenchymal Stem Cells-Mediated Cardiac Repair
Hypoxia-Inducible Factor 1 Alpha Contributes to Cardiac Healing in Mesenchymal Stem Cells-Mediated Cardiac Repair
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DOI：
10.1089/scd.2012.0340
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发表时间：
2013-02-01
影响因子：
4
通讯作者：
Sepulveda, Pilar
中科院分区：
文献类型：
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作者：
Cerrada, Inmaculada;Ruiz-Sauri, Amparo;Sepulveda, Pilar
间充质干细胞 (MSC) 可有效治疗心肌梗塞 (MI)，之前的报告表明，缺氧可改善 MSC 的自我更新和治疗效果。考虑到缺氧诱导因子 1 α (HIF-1 α) 是缺氧适应性反应的主要调节因子，我们假设 MSC 中 HIF-1 α 的过度表达可以模拟缺氧触发的一些机制，并在没有缺氧刺激的情况下增加其治疗潜力。用 HIF-1 α 慢病毒载体 (MSC-HIF) 转导 MSC 导致细胞粘附和迁移增加，并激活编码旁分泌因子的靶基因。当MSC-HIF向梗塞裸鼠心肌内注射时，发现（用MSC-HIF治疗梗塞大鼠后）心功能、血管生成、心肌细胞增殖和纤维化组织减少方面显着改善，且不诱导心脏肥大。这一发现为 HIF-1 α 对 MSC 生物学的关键作用提供了证据，并表明 HIF-1 α 的稳定性可作为细胞治疗的新策略。
Mesenchymal stem cells (MSC) are effective in treating myocardial infarction (MI) and previous reports demonstrated that hypoxia improves MSC self-renewal and therapeutics. Considering that hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a master regulator of the adaptative response to hypoxia, we hypothesized that HIF-1 alpha overexpression in MSC could mimic some of the mechanisms triggered by hypoxia and increase their therapeutic potential without hypoxia stimulation. Transduction of MSC with HIF-1 alpha lentivirus vectors (MSC-HIF) resulted in increased cell adhesion and migration, and activation of target genes coding for paracrine factors. When MSC-HIF were intramyocardially injected in infarcted nude rats, significant improvement was found (after treatment of infarcted rats with MSC-HIF) in terms of cardiac function, angiogenesis, cardiomyocyte proliferation, and reduction of fibrotic tissue with no induction of cardiac hypertrophy. This finding provides evidences for a crucial role of HIF-1 alpha on MSC biology and suggests the stabilization of HIF-1 alpha as a novel strategy for cellular therapies.