Wip1 knockout inhibits the proliferation and enhances the migration of bone marrow mesenchymal stem cells
Wip1 knockout inhibits the proliferation and enhances the migration of bone marrow mesenchymal stem cells
复制标题
Wip1敲除抑制骨髓间充质干细胞增殖并增强迁移
DOI：
10.1016/j.yexcr.2015.03.018
复制
发表时间：
2015-06-10
影响因子：
3.7
通讯作者：
Li, Kui
中科院分区：
文献类型：
--
作者：
Tang, Yiting;Liu, Lan;Li, Kui
骨髓间充质干细胞（MSC）是一种起源于骨髓的多能成体祖细胞，在多功能治疗中具有重要作用。然而，MSC在体外的生长停滞和过早衰老阻止了这些细胞的深入表征。此外，参与MSC迁移的调节因素在很大程度上仍然未知。鉴于蛋白磷酸化与MSC增殖和迁移过程相关，我们在本研究中将重点放在野生型p53诱导型磷酸酶-1（Wip 1）上，这是一种经过充分研究的磷酸化调节剂。我们的研究结果表明，Wip 1基因敲除显着抑制骨髓间充质干细胞的增殖和诱导G2期细胞周期阻滞通过减少cyclinB 1的表达。与WT-MSCs相比，Wip 1（-/-）MSCs在体外培养6代后出现早期生长停滞。Transwell和划痕试验显示Wip 1（-/-）MSC比WT-MSC迁移更有效。此外，Wip 1（-/-）MSC的迁移反应增强可能归因于诱导Rac 1-GTP活性、pAKT/AKT比率、粘附性肌动蛋白（f-actin）重排和丝状伪足形成的增加。基于这些结果，我们然后检查了用PI 3 K/AKT和Rac 1抑制剂处理的效果，这两种抑制剂都损害了MSC的迁移活性。因此，我们认为PI 3 K/AKT/Rac 1信号轴介导Wip 1基因敲除诱导的MSC迁移。我们的研究结果表明，Wip 1在MSC转化中的主要功能是维持增殖能力。然而，敲除Wip 1增加了MSC的迁移能力。Wip 1的这种双重作用为MSC的有目的的路由提供了潜力。(C)2015 Elsevier Inc. All rights reserved.
Mesenchymal stem cells (MSCs), a unique population of multipotent adult progenitor cells originally found in bone marrow (BM), are extremely useful for multifunctional therapeutic approaches. However, the growth arrest and premature senescence of MSCs in vitro prevent the in-depth characterization of these cells. In addition, the regulatory factors involved in MSCs migration remain largely unknown. Given that protein phosphorylation is associated with the processes of MSCs proliferation and migration, we focused on wild-type p53-inducible phosphatase-1 (Wip1), a well-studied modulator of phosphorylation, in this study. Our results showed that Wip1 knockout significantly inhibited MSCs proliferation and induced G2-phase cell-cycle arrest by reducing cyclinB1 expression. Compared with WT-MSCs, Wip1(-/-) MSCs displayed premature growth arrest after six passages in culture. Transwell and scratch assays revealed that Wip1(-/-) MSCs migrate more effectively than WT-MSCs. Moreover, the enhanced migratory response of Wip1(-/-) MSCs may be attributed to increases in the induction of Rac1-GTP activity, the pAKT/AKT ratio, the rearrangement of filamentous-actin (f-actin), and filopodia formation. Based on these results, we then examined the effect of treatment with a PI3K/AKT and Rac1 inhibitor, both of which impaired the migratory activity of MSCs. Therefore, we propose that the PI3K/AKT/Rac1 signaling axis mediates the Wip1 knockout-induced migration of MSCs. Our findings indicate that the principal function of Wip1 in MSCs transformation is the maintenance of proliferative capacity. Nevertheless, knocking out Wip1 increases the migratory capacity of MSCs. This dual effect of Wip1 provides the potential for purposeful routing of MSCs. (C) 2015 Elsevier Inc. All rights reserved.