Inhibiting actin depolymerization enhances osteoblast differentiation and bone formation in human stromal stem cells
Inhibiting actin depolymerization enhances osteoblast differentiation and bone formation in human stromal stem cells
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DOI：
10.1016/j.scr.2015.06.009
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发表时间：
2015-09-01
影响因子：
1.2
通讯作者：
Kassem, Moustapha
中科院分区：
文献类型：
--
作者：
Chen, Li;Shi, Kaikai;Kassem, Moustapha
通过肌动蛋白动力学的肌动蛋白细胞骨架的重塑涉及许多生物过程，但其在人基质（骨骼）干细胞（hMSCs）分化中的作用知之甚少。在本研究中，我们证明了通过抑制hMSCs中两种主要肌动蛋白解聚因子（ADF）：Cofilin 1（CFL 1）和Destrin（Dostrin）的基因表达来稳定肌动蛋白丝，可以增强细胞活力和体外成骨细胞（OB）分化，以及体内异位骨形成。类似地，用鬼笔环肽处理hMSC，已知鬼笔环肽稳定聚合的肌动蛋白丝，增加hMSC活力和OB分化。相反地，细胞分裂素D，一种肌动蛋白聚合的抑制剂，降低细胞活力并抑制hMSC的成骨分化。在分子水平上，通过抑制LIM结构域激酶1（LIMK1）来阻止Cofilin磷酸化降低了细胞活力并损害了hMSC的成骨分化。此外，肌动蛋白解聚减少了hMSC成骨分化过程中FAK、p38和JNK的活化，而肌动蛋白聚合则增强了这些信号通路。我们的研究结果表明，肌动蛋白动态重组和Cofilin磷酸化环参与控制hMSC增殖和成骨细胞分化。(C)2015作者由爱思唯尔公司出版
Remodeling of the actin cytoskeleton through actin dynamics is involved in a number of biological processes, but its role in human stromal (skeletal) stemcells (hMSCs) differentiation is poorly understood. In the present study, we demonstrated that stabilizing actin filaments by inhibiting gene expression of the two main actin depolymerizing factors (ADFs): Cofilin 1 (CFL1) and Destrin (DSTN) in hMSCs, enhanced cell viability and differentiation into osteoblastic cells (OB) in vitro, as well as heterotopic bone formation in vivo. Similarly, treating hMSC with Phalloidin, which is known to stabilize polymerized actin filaments, increased hMSCs viability and OB differentiation. Conversely, Cytocholasin D, an inhibitor of actin polymerization, reduced cell viability and inhibited OB differentiation of hMSC. At a molecular level, preventing Cofilin phosphorylation through inhibition of LIM domain kinase 1 (LIMK1) decreased cell viability and impaired OB differentiation of hMSCs. Moreover, depolymerizing actin reduced FAK, p38 and JNK activation during OB differentiation of hMSCs, while polymerizing actin enhanced these signaling pathways. Our results demonstrate that the actin dynamic reassembly and Cofilin phosphorylation loop is involved in the control of hMSC proliferation and osteoblasts differentiation. (C) 2015 The Authors. Published by Elsevier B.V.