Introduction: A feature which makes stem cells promising candidates for cell therapy is their ability to migrate\r\neffectively into damaged or diseased tissues. Recent reports demonstrated the increased motility of human\r\nmesenchymal stem cells (hMSC) grown under hypoxic conditions compared to normoxic cells. However, the\r\ndirectional migration of hMSC cultured in hypoxia has not been investigated. In this study we examined the in\r\nvitro transmembrane migration of hMSC permanently cultured in hypoxia in response to various cytokines. We also\r\nstudied the involvement of RhoA, a molecule believed to play an essential role in the migration of MSC via\r\nreorganization of the cytoskeleton.\r\nMethods: We compared the directional migration of human hMSCs grown permanently under normal (21%,\r\nnormoxic) and low O2 (5%, hypoxic) conditions until passage 4 using an in vitro transmembrane migration assay. A\r\nseries of 17 cytokines was used to induce chemotaxis. We also compared the level of GTP-bound RhoA in the cell\r\nextracts of calpeptin-activated hypoxic and normoxic hMSC.\r\nResults: We found that hMSC cultured in hypoxia demonstrate markedly higher targeted migration activity\r\ncompared to normoxic cells, particularly towards wound healing cytokines, including those found in ischemic and\r\nmyocardial infarction. We also demonstrated for the first time that hMSC are dramatically more sensitive to\r\nactivation of RhoA.\r\nConclusions: The results of this study indicate that high directional migration of hMSCs permanently grown in\r\nhypoxia is associated with the enhanced activation of RhoA. The enhanced migratory capacity of hypoxic hMSC\r\nwould further suggest their potential advantages for clinical applications.
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