Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis.
Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis.
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DOI：
10.3390/ijms18061320
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发表时间：
2017-06-21
影响因子：
5.6
通讯作者：
Lee SH
中科院分区：
文献类型：
--
作者：
Lee JH;Yoon YM;Lee SH
间充质干细胞（MSC）是干细胞治疗的理想材料。由于间充质干细胞生活在低氧微环境中（低氧张力为1%至7%），一些研究关注了缺氧预处理对间充质干细胞存活的有益影响；然而，这种影响背后的机制尚不清楚。本研究旨在揭示78-kDa葡萄糖调节蛋白（GRP78）在后肢缺血中增强MSC生物活性和存活的潜在机制。在低氧条件下（2% O2）， GRP78通过缺氧诱导因子(HIF)-1α表达显著升高。缺氧诱导的GRP78通过HIF-1α-GRP78-Akt信号轴促进MSCs的增殖和迁移潜能。在小鼠后肢缺血模型中，缺氧预处理通过抑制细胞死亡信号通路和增加血管生成细胞因子分泌来增强移植间充质干细胞的存活和增殖。这些作用受GRP78调控。我们的研究结果表明，缺氧预处理通过HIF-1α-GRP78-Akt信号通路促进MSCs的存活、增殖和血管生成细胞因子的分泌，这表明缺氧预处理的MSCs可能为基于MSCs的治疗提供了一种治疗策略，GRP78代表了功能性MSCs发育的潜在靶点。
Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such effects remain unclear. This study aimed to uncover the potential mechanism involving 78-kDa glucose-regulated protein (GRP78) to explain the enhanced MSC bioactivity and survival in hindlimb ischemia. Under hypoxia (2% O2), the expression of GRP78 was significantly increased via hypoxia-inducible factor (HIF)-1α. Hypoxia-induced GRP78 promoted the proliferation and migration potential of MSCs through the HIF-1α-GRP78-Akt signal axis. In a murine hind-limb ischemia model, hypoxic preconditioning enhanced the survival and proliferation of transplanted MSCs through suppression of the cell death signal pathway and augmentation of angiogenic cytokine secretion. These effects were regulated by GRP78. Our findings indicate that hypoxic preconditioning promotes survival, proliferation, and angiogenic cytokine secretion of MSCs via the HIF-1α-GRP78-Akt signal pathway, suggesting that hypoxia-preconditioned MSCs might provide a therapeutic strategy for MSC-based therapies and that GRP78 represents a potential target for the development of functional MSCs.