High targeted migration of human mesenchymal stem cells grown in hypoxia is associated with enhanced activation of RhoA.
High targeted migration of human mesenchymal stem cells grown in hypoxia is associated with enhanced activation of RhoA.
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DOI：
10.1186/scrt153
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发表时间：
2013-01-07
影响因子：
7.5
通讯作者：
Kharazi A
中科院分区：
文献类型：
--
作者：
Vertelov G;Kharazi L;Muralidhar MG;Sanati G;Tankovich T;Kharazi A
使干细胞成为细胞治疗的有希望候选者的一个特征是它们有效迁移到受损或患病组织中的能力。最近的报告表明，增加的人骨髓间充质干细胞（hMSC）生长在缺氧条件下的运动相比，常氧细胞。然而，在缺氧条件下培养的hMSC的定向迁移尚未被研究。在这项研究中，我们研究了在体外跨膜迁移的hMSC永久培养在缺氧中响应各种细胞因子。我们还研究了RhoA的参与，RhoA是一种被认为在MSC通过细胞骨架重组的迁移中起重要作用的分子。我们使用体外跨膜迁移试验比较了在正常（21%，常氧）和低氧（5%，缺氧）条件下永久生长的人hMSCs的定向迁移，直到第4代。使用一系列17种细胞因子诱导趋化性。我们还比较了钙蛋白酶激活的低氧和常氧hMSC的细胞提取物中GTP结合的RhoA的水平。我们发现，在缺氧中培养的hMSC表现出明显更高的靶向迁移活性相比，含氧量正常的细胞，特别是对伤口愈合细胞因子，包括那些在缺血性和心肌梗死。我们还首次证明了hMSC对RhoA的激活显着更敏感。这项研究的结果表明，在缺氧条件下永久生长的hMSCs的高定向迁移与RhoA的激活增强有关。低氧hMSC迁移能力的增强将进一步表明其临床应用的潜在优势。
A feature which makes stem cells promising candidates for cell therapy is their ability to migrate effectively into damaged or diseased tissues. Recent reports demonstrated the increased motility of human mesenchymal stem cells (hMSC) grown under hypoxic conditions compared to normoxic cells. However, the directional migration of hMSC cultured in hypoxia has not been investigated. In this study we examined the in vitro transmembrane migration of hMSC permanently cultured in hypoxia in response to various cytokines. We also studied the involvement of RhoA, a molecule believed to play an essential role in the migration of MSC via reorganization of the cytoskeleton. We compared the directional migration of human hMSCs grown permanently under normal (21%, normoxic) and low O2 (5%, hypoxic) conditions until passage 4 using an in vitro transmembrane migration assay. A series of 17 cytokines was used to induce chemotaxis. We also compared the level of GTP-bound RhoA in the cell extracts of calpeptin-activated hypoxic and normoxic hMSC. We found that hMSC cultured in hypoxia demonstrate markedly higher targeted migration activity compared to normoxic cells, particularly towards wound healing cytokines, including those found in ischemic and myocardial infarction. We also demonstrated for the first time that hMSC are dramatically more sensitive to activation of RhoA. The results of this study indicate that high directional migration of hMSCs permanently grown in hypoxia is associated with the enhanced activation of RhoA. The enhanced migratory capacity of hypoxic hMSC would further suggest their potential advantages for clinical applications.