Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells
Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells
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DOI：
10.1634/stemcells.2007-1104
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发表时间：
2008-08-01
期刊：
影响因子：
5.2
通讯作者：
Nolta, Jan A.
中科院分区：
文献类型：
--
作者：
Rosova, Ivana;Dao, Mo;Nolta, Jan A.
间充质干细胞（MSC）是在骨髓、脂肪组织和其它成人组织中发现的成人多能细胞。MSC已被证明可以改善体内损伤组织的再生，但其机制仍不清楚。通常，MSC在环境或常氧条件（21%氧）下培养。然而，MSC在骨髓和其他部位的生理小生境具有低得多的氧张力。当用作修复组织损伤的治疗工具时，在标准条件下培养的MSC必须从培养物中的21%氧气适应到缺血组织中的低于1%氧气。因此，我们研究了在低氧条件下（1%-3%氧气）预培养人骨髓来源的MSC的效果，以阐明增强其组织再生潜力的最佳条件。我们证明了在低氧条件下培养的MSC激活Akt信号通路，同时保持其活力和细胞周期速率。我们还发现，在缺氧条件下培养的MSC诱导表达cMet，肝细胞生长因子（HGF）的主要受体，并增强cMet信号。在低氧条件下培养的MSC增加了它们的迁移率。由于迁移和HGF反应性被认为是体内MSC募集和/或活化的关键介质，我们接下来使用鼠后肢缺血模型检查了在缺氧条件下培养的MSC的组织再生潜力。我们发现，在这个模型中，局部表达的肝细胞生长因子增加缺血肌肉。与生理盐水对照组相比，在手术诱导后肢缺血后24小时，动脉内注射在常氧或缺氧条件下培养的MSC增强了血管再生。然而，在注射了低氧预处理MSC的小鼠中，血流的恢复明显更早。总的来说，这些数据表明，移植前在缺氧条件下预培养MSC可提高其组织再生潜力。
Alesenchymal stem cells (MSC) are adult multipotent cells found in bone marrow, adipose tissue, and other adult tissues. MSC have been shown to improve regeneration of injured tissues in vivo, but the mechanisms remain unclear. Typically, MSC are cultured under ambient, or normoxic, conditions (21% oxygen). However, the physiological niches for MSC in the bone marrow and other sites have much lower oxygen tension. When used as a therapeutic tool to repair tissue injuries, MSC cultured in standard conditions must adapt from 21% oxygen in culture to less than 1% oxygen in the ischemic tissue. We therefore examined the effects of preculturing human bone marrow-derived MSC in hypoxic conditions (1%-3% oxygen) to elucidate the best conditions that enhance their tissue regenerative potential. We demonstrated that MSC cultured in hypoxia activate the Akt signaling pathway while maintaining their viability and cell cycle rates. We also showed that MSC cultured in hypoxia induced expression of cMet, the major receptor for hepatocyte growth factor (HGF), and enhanced cMet signaling. MSC cultured in hypoxic conditions increased their migration rates. Since migration and HGF responsiveness are thought to be key mediators of MSC recruitment and/or activation in vivo, we next examined the tissue regenerative potential of MSC cultured under hypoxic conditions, using a murine hind limb ischemia model. We showed that local expression of HGF is increased in ischemic muscle in this model. Intra-arterial injection of MSC cultured in either normoxic or hypoxic conditions 24 hours after surgical induction of hind limb ischemia enhanced revascularization compared with saline controls. However, restoration of blood flow was observed significantly earlier in mice that had been injected with hypoxic preconditioned MSC. Collectively, these data suggest that preculturing MSC under hypoxic conditions prior to transplantation improves their tissue regenerative potential.