Integrins α2β1 and α11β1 regulate the survival of mesenchymal stem cells on collagen I.
Integrins α2β1 and α11β1 regulate the survival of mesenchymal stem cells on collagen I.
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DOI：
10.1038/cddis.2011.71
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发表时间：
2011-07-28
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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虽然间充质干细胞（MSC）是骨再生的天然来源，但MSC与胶原蛋白I相互作用的确切机制尚未发现。细胞与I型胶原的粘附主要由三种整合素受体α1β1、α2β1和α11β1介导。使用人MSC（hMSC），我们发现α11亚基表现出最高的基础表达水平，但在成骨刺激下，α2和α11整合素均显著上调。为了阐明胶原结合整合素的可能作用，我们在hMSC中应用短发夹RNA（shRNA）介导的敲低，发现α2或α11缺陷，而不是α1，导致hMSC数量的巨大减少，这是由于线粒体渗漏伴随着Bcl-2相关的X蛋白上调。为了阐明hMSC中胶原结合整合素所传递的信号，我们分析了黏着斑激酶、细胞外信号调节蛋白激酶和丝氨酸/苏氨酸蛋白激酶B（PKB/Akt）激酶的活化，并且仅在α2-和α11-shRNA hMSC中检测到Akt磷酸化显著降低。最后，用来自阿尔茨海默病患者的hMSC进行的实验显示α2整联蛋白的显著下调伴随着线粒体通透性的增加。总之，我们的研究首次描述了α2β1或α11β1介导的与I型胶原相互作用的干扰导致MSC细胞死亡，并敦促进一步研究MSC在I型胶原异常的骨条件下的影响。
Although mesenchymal stem cells (MSCs) are the natural source for bone regeneration, the exact mechanisms governing MSC crosstalk with collagen I have not yet been uncovered. Cell adhesion to collagen I is mostly mediated by three integrin receptors – α1β1, α2β1 and α11β1. Using human MSC (hMSC), we show that α11 subunit exhibited the highest basal expression levels but on osteogenic stimulation, both α2 and α11 integrins were significantly upregulated. To elucidate the possible roles of collagen-binding integrins, we applied short hairpin RNA (shRNA)-mediated knockdown in hMSC and found that α2 or α11 deficiency, but not α1, results in a tremendous reduction of hMSC numbers owing to mitochondrial leakage accompanied by Bcl-2-associated X protein upregulation. In order to clarify the signaling conveyed by the collagen-binding integrins in hMSC, we analyzed the activation of focal adhesion kinase, extracellular signal-regulated protein kinase and serine/threonine protein kinase B (PKB/Akt) kinases and detected significantly reduced Akt phosphorylation only in α2- and α11-shRNA hMSC. Finally, experiments with hMSC from osteoporotic patients revealed a significant downregulation of α2 integrin concomitant with an augmented mitochondrial permeability. In conclusion, our study describes for the first time that disturbance of α2β1- or α11β1-mediated interactions to collagen I results in the cell death of MSCs and urges for further investigations examining the impact of MSCs in bone conditions with abnormal collagen I.
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DOI：
10.1083/jcb.144.6.1337
发表时间：
1999-03-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Farrelly N;Lee YJ;Oliver J;Dive C;Streuli CH
通讯作者：
Streuli CH
影响因子：
5.3
作者：
Docheva D;Padula D;Popov C;Mutschler W;Clausen-Schaumann H;Schieker M
通讯作者：
Schieker M
影响因子：
2.7
作者：
Popova, SN;Rodriguez-Sánchez, B;Gullberg, D
通讯作者：
Gullberg, D
影响因子：
3.2
作者：
Nilsson, SK;Debatis, ME;Becker, PS
通讯作者：
Becker, PS
影响因子：
6
作者：
Chen, JC;Diacovo, TG;Zutter, MM
通讯作者：
Zutter, MM