The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-β.
The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-β.
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DOI：
10.1016/j.biomaterials.2011.02.019
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发表时间：
2011-06
期刊：
影响因子：
14
通讯作者：
Li, Song
中科院分区：
文献类型：
--
作者：
Park, Jennifer S.;Chu, Julia S.;Tsou, Anchi D.;Diop, Rokhaya;Tang, Zhenyu;Wang, Aijun;Li, Song
关键词：
骨髓间充质干细胞(MSCs)是组织工程和再生医学的重要细胞来源。转化生长因子β(转化生长因子-β)可促进间充质干细胞向平滑肌细胞或软骨细胞分化。在这里，我们展示了矩阵的刚性调制了这些差异效应。与硬基质相比，软基质上的MSCs铺展较少，应力纤维较少，增殖率较低。硬基质上的骨髓间充质干细胞有较高的α-肌动蛋白和钙蛋白-1的表达，而软质基质上的骨髓间充质干细胞有较高的成软骨标记物II型胶原和成脂标记物脂蛋白脂酶的表达。转化生长因子-β增加刚性底物上SMC标志物的表达。而转化生长因子-β增加了软基质上的成软骨标记物，抑制了成脂标记物的形成，而成脂基质和软基质有效地诱导了成脂分化。Rho GTP酶参与了上述所有谱系标记的表达，但不能解释基质刚性的差异效应。此外，软底物对Rho活性没有显著影响，但抑制了Rho诱导的应力纤维形成和α-肌动蛋白组装。进一步分析表明，在软基质上的MSCs具有较弱的细胞黏附能力，并且细胞黏附强度的抑制与软基质对谱系标志表达的影响相似。这些结果提供了关于基质硬度如何不同地调节干细胞分化的见解，并对设计具有适当机械性能的生物材料以用于组织再生具有重要意义。
Bone marrow mesenchymal stem cells (MSCs) are a valuable cell source for tissue engineering and regenerative medicine. Transforming growth factor β (TGF-β) can promote MSC differentiation into either smooth muscle cells (SMCs) or chondrogenic cells. Here we showed that matrix stiffness modulated these differential effects. MSCs on soft substrates had less spreading, fewer stress fibers and lower proliferation rate than MSCs on stiff substrates. MSCs on stiff substrates had higher expression of SMC markers α-actin and calponin-1; in contrast, MSCs on soft substrates had a higher expression of chondrogenic marker collagen-II and adipogenic marker lipoprotein lipase (LPL). TGF-β increased SMC marker expression on stiff substrates. However, TGF-β increased chondrogenic marker and suppressed adipogenic marker on the soft substrates, while adipogenic medium and soft substrates induced adipogenic differentiation effectively. Rho GTPase was involved in the expression of all aforementioned lineage markers, but did not account for the differential effects of matrix stiffness. In addition, soft substrates did not significantly affect Rho activity, but inhibited Rho-induced stress fiber formation and α-actin assembly. Further analysis showed that MSCs on soft matrices had weaker cell adhesion, and that the suppression of cell adhesion strength mimicked the effects of soft substrates on the lineage marker expression. These results provide insights of how matrix stiffness differentially regulates stem cell differentiation, and have significant implications for the design of biomaterials with appropriate mechanical property for tissue regeneration.
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