Aging-related Decrease of Human ASC Angiogenic Potential Is Reversed by Hypoxia Preconditioning Through ROS Production
Aging-related Decrease of Human ASC Angiogenic Potential Is Reversed by Hypoxia Preconditioning Through ROS Production
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DOI：
10.1038/mt.2012.213
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发表时间：
2013-02-01
影响因子：
12.4
通讯作者：
Planat-Benard, Valerie
中科院分区：
文献类型：
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作者：
De Barros, Sandra;Dehez, Stephanie;Planat-Benard, Valerie
脂肪基质/干细胞(ASC)是细胞治疗的理想自体细胞来源。它们的移植增强了实验性缺血损伤后的新生血管。衰老与骨髓间充质干细胞(MSCs)再生能力的进行性降低有关。本工作旨在确定衰老对人ASC能力的影响。首先，在小鼠后肢缺血模型中，我们证明了衰老对人ASC(HASC)血管生成能力的损害。尽管HASC的数量、表型和增殖没有随着年龄的增长而改变，但在体外已经发现了几种与衰老的不利影响有关的机制，包括伴随着(I)ASC向内皮细胞分化能力的下降，(Ii)促血管生成和有利于生存的因子的分泌，以及(Iii)氧化应激。这些影响被低氧预适应所抵消，低氧预适应改善了来自老年供者的HASC在体内的血管生成能力，而来自具有较强管理低氧应激能力的年轻供者的HASC则没有。最后，我们确定ROS的产生是低氧对HASC血管生成能力的一个关键信号。本研究首次证明，供体的年龄损害了缺血肌肉中HASC的血管生成能力，并通过低氧预适应改变了ROS的产生，从而逆转了衰老的不利影响。
Adipose stroma/stem cells (ASC) represent an ideal source of autologous cells for cell-based therapy. Their transplantation enhances neovascularization after experimental ischemic injury. Aging is associated with a progressive decrease in the regenerative potential of mesenchymal stem cells (MSCs) from bone marrow. This work aims to determine the aging effect on human ASC capacities. First, we show that aging impairs angiogenic capacities of human ASC (hASC) in a mouse ischemic hindlimb model. Although no change in hASC number, phenotype, and proliferation was observed with aging, several mechanisms involved in the adverse effects of aging have been identified in vitro combining a concomitant decrease in (i) ASC ability to differentiate towards endothelial cells, (ii) secretion of proangiogenic and pro-survival factors, and (iii) oxidative stress. These effects were counteracted by a hypoxic preconditioning that improved in vivo angiogenic capacities of hASC from older donors, while hASC from young donors that have a strong ability to manage hypoxic stress were not. Finally, we identified reactive oxygen species (ROS) generation as a key signal of hypoxia on hASC angiogenic capacities. This study demonstrates for the first time that age of donor impaired angiogenic capacities of hASC in ischemic muscle and change in ROS generation by hypoxic preconditioning reverse the adverse effect of aging.