TRPV4-mediates oscillatory fluid shear mechanotransduction in mesenchymal stem cells in part via the primary cilium.
TRPV4-mediates oscillatory fluid shear mechanotransduction in mesenchymal stem cells in part via the primary cilium.
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DOI：
10.1038/s41598-018-22174-3
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发表时间：
2018-02-28
影响因子：
4.6
通讯作者：
Hoey DA
中科院分区：
文献类型：
--
作者：
Corrigan MA;Johnson GP;Stavenschi E;Riffault M;Labour MN;Hoey DA
骨骼动态平衡需要从间充质干细胞(MSC)群体中持续补充形成骨的成骨细胞，这一过程已被证明是机械调节的。然而，生物物理刺激可以诱导生化信号变化的机制，即机械转导，却知之甚少。作为负载诱导成骨的先驱，破译MSC成骨的分子机制是开发新型合成代谢疗法的关键一步。因此，在本研究中，我们研究了机械敏感的钙通道瞬时受体V亚家族成员4(TRPV4)在MSCs中的表达，并证明TRPV4定位于高应变区域，特别是初级纤毛。我们证明TRPV4是MSC机械转导、介导振荡流体剪切诱导的钙信号和早期成骨基因表达所必需的。此外，我们证明了TRPV4可以被药物激活，引起与机械刺激相同的反应。最后，我们发现TRPV4在初级纤毛上的定位具有重要的功能意义，初级纤毛缺陷的MSCs对TRPV4的激活表现出抑制的成骨反应。总而言之，这些数据表明了一种新的干细胞机械转导机制，可以用于治疗，并进一步强调了初级纤毛在MSC生物学中的关键作用。
Skeletal homeostasis requires the continued replenishment of the bone forming osteoblast from a mesenchymal stem cell (MSC) population, a process that has been shown to be mechanically regulated. However, the mechanisms by which a biophysical stimulus can induce a change in biochemical signaling, mechanotransduction, is poorly understood. As a precursor to loading-induced bone formation, deciphering the molecular mechanisms of MSC osteogenesis is a critical step in developing novel anabolic therapies. Therefore, in this study we characterize the expression of the mechanosensitive calcium channel Transient Receptor Potential subfamily V member 4 (TRPV4) in MSCs and demonstrate that TRPV4 localizes to areas of high strain, specifically the primary cilium. We demonstrate that TRPV4 is required for MSC mechanotransduction, mediating oscillatory fluid shear induced calcium signaling and early osteogenic gene expression. Furthermore, we demonstrate that TRPV4 can be activated pharmacologically eliciting a response that mirrors that seen with mechanical stimulation. Lastly, we show that TRPV4 localization to the primary cilium is functionally significant, with MSCs with defective primary cilia exhibiting an inhibited osteogenic response to TRPV4 activation. Collectively, this data demonstrates a novel mechanism of stem cell mechanotransduction, which can be targeted therapeutically, and further highlights the critical role of the primary cilium in MSC biology.
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影响因子：
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作者：
Lee KL;Guevarra MD;Nguyen AM;Chua MC;Wang Y;Jacobs CR
通讯作者：
Jacobs CR
影响因子：
2.4
作者：
Irianto, Jerome;Ramaswamy, Girish;Serra, Rosa;Knight, Martin M.
通讯作者：
Knight, Martin M.
影响因子：
7.8
作者：
Koetttgen, Michael;Buchholz, Bjoern;Garcia-Gonzalez, Miguel A.;Kotsis, Fruzsina;Fu, Xiao;Doerken, Mara;Boehlke, Christopher;Steffl, Daniel;Tauber, Robert;Wegierski, Tomasz;Nitschke, Roland;Suzuki, Makoto;Kramer-Zucker, Albrecht;Germino, Gregory G.;Watnick, Terry;Prenen, Jean;Nilius, Bernd;Kuehn, E. Wolfgang;Walz, Gerd
通讯作者：
Walz, Gerd
影响因子：
2.9
作者：
Hoeger, Ulli;Meisner, Shannon;French, Andrew S.
通讯作者：
French, Andrew S.
DOI：
10.1073/pnas.202296599
发表时间：
2002-10-01
影响因子：
11.1
作者：
Bancroft, GN;Sikavitsast, VI;Mikos, AG
通讯作者：
Mikos, AG