Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells.
Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells.
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DOI：
10.1186/s13287-018-1007-x
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发表时间：
2018-10-11
影响因子：
7.5
通讯作者：
Cancio LC
中科院分区：
文献类型：
--
作者：
Antebi B;Rodriguez LA 2nd;Walker KP 3rd;Asher AM;Kamucheka RM;Alvarado L;Mohammadipoor A;Cancio LC
在骨髓中，MSC驻留在低氧环境（1- 5%O2）中，这被认为可以保持其多能状态。通常，MSC的体外扩增是在常氧（~ 21%O2）下进行的，这是一个已被证明会损害其功能的过程。在这里，我们评估了在缺氧条件下培养的MSC的特性和功能，并假设与常氧相比，专用缺氧将增强MSC的功能特性。人和猪骨髓间充质干细胞从新鲜的单核细胞获得。第一项研究评估了长期（10天）和短期（48小时）缺氧（1%O2）培养后MSC的功能。在我们的第二项研究中，我们评估了短期2%和5%缺氧条件下培养的MSC的功能特征。评估MSC的代谢活性、增殖、存活力、克隆形成、基因表达和分泌能力。在长期培养中，常见的MSC表面标志物（CD 44和CD 105）表达在缺氧下下降。此外，在长期培养中，MSC增殖明显较慢，并且在缺氧条件下产量较低。相反，在短期培养中，MSC在缺氧条件下增殖明显更快。在长期和短期培养中，MSC代谢活性在缺氧条件下显著升高。此外，在缺氧条件下培养的MSC具有上调的VEGF表达，同时下调HMGB 1和凋亡基因BCL-2和CASP 3。最后，在两种缺氧培养中，促炎细胞因子IL-8被抑制，而抗炎因子IL-1 ra和GM-CSF的水平仅在短期缺氧中升高。在这项研究中，我们证明了缺氧增强了猪和人MSC的治疗特性。然而，短期2%的缺氧提供了最大的整体效益，例如与常氧相比，增殖，自我更新能力，关键基因和炎症环境的调节增加。这些数据对于产生具有增强功能的稳健MSC用于临床应用是重要的。
In the bone marrow, MSCs reside in a hypoxic milieu (1–5% O2) that is thought to preserve their multipotent state. Typically, in vitro expansion of MSCs is performed under normoxia (~ 21% O2), a process that has been shown to impair their function. Here, we evaluated the characteristics and function of MSCs cultured under hypoxia and hypothesized that, when compared to normoxia, dedicated hypoxia will augment the functional characteristics of MSCs. Human and porcine bone marrow MSCs were obtained from fresh mononuclear cells. The first study evaluated MSC function following both long-term (10 days) and short-term (48 h) hypoxia (1% O2) culture. In our second study, we evaluated the functional characteristics of MSC cultured under short-term 2% and 5% hypoxia. MSCs were evaluated for their metabolic activity, proliferation, viability, clonogenicity, gene expression, and secretory capacity. In long-term culture, common MSC surface marker expression (CD44 and CD105) dropped under hypoxia. Additionally, in long-term culture, MSCs proliferated significantly slower and provided lower yields under hypoxia. Conversely, in short-term culture, MSCs proliferated significantly faster under hypoxia. In both long-term and short-term cultures, MSC metabolic activity was significantly higher under hypoxia. Furthermore, MSCs cultured under hypoxia had upregulated expression of VEGF with concomitant downregulation of HMGB1 and the apoptotic genes BCL-2 and CASP3. Finally, in both hypoxia cultures, the pro-inflammatory cytokine, IL-8, was suppressed, while levels of the anti-inflammatories, IL-1ra and GM-CSF, were elevated in short-term hypoxia only. In this study, we demonstrate that hypoxia augments the therapeutic characteristics of both porcine and human MSCs. Yet, short-term 2% hypoxia offers the greatest benefit overall, exemplified by the increase in proliferation, self-renewing capacity, and modulation of key genes and the inflammatory milieu as compared to normoxia. These data are important for generating robust MSCs with augmented function for clinical applications.
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影响因子：
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作者：
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作者：
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