Geometric cues for directing the differentiation of mesenchymal stem cells
Geometric cues for directing the differentiation of mesenchymal stem cells
复制标题
DOI：
10.1073/pnas.0903269107
复制
发表时间：
2010-03-16
影响因子：
11.1
通讯作者：
Mrksich, Milan
中科院分区：
文献类型：
--
作者：
Kilian, Kristopher A.;Bugarija, Branimir;Mrksich, Milan
已经针对理解影响干细胞谱系定型的因素做出了重大努力。本文证明，细胞形状对骨髓间充质干细胞（MSC）的分化有很大影响，与可溶性因子无关。当暴露在竞争性可溶性分化信号中时，培养在长宽比增加的矩形和五边形对称但具有不同亚细胞曲率的形状中的细胞，并且每个细胞占据相同的面积，显示出不同的脂肪生成和骨生成特征。结果表明，增加肌动球蛋白收缩性的几何特征促进骨生成，并且与分化细胞的微环境的体内特征一致。细胞分裂破坏药物调节谱系定型中基于形状的趋势，验证了分化过程中粘着斑和肌球蛋白产生的收缩性的关键作用。微阵列分析和通路抑制研究表明，收缩细胞通过增强c-Jun N-末端激酶（JNK）和细胞外相关激酶（ERK 1/2）激活以及升高的无翅型（Wnt）信号传导来促进骨生成。总而言之，这项工作指出了几何形状线索在协调机械化学信号和旁分泌/自分泌因子方面可以发挥的作用，这些信号和因子可以将MSC引导到适当的命运。
Significant efforts have been directed to understanding the factors that influence the lineage commitment of stem cells. This paper demonstrates that cell shape, independent of soluble factors, has a strong influence on the differentiation of human mesenchymal stem cells (MSCs) from bone marrow. When exposed to competing soluble differentiation signals, cells cultured in rectangles with increasing aspect ratio and in shapes with pentagonal symmetry but with different subcellular curvature-and with each occupying the same area-display different adipogenesis and osteogenesis profiles. The results reveal that geometric features that increase actomyosin contractility promote osteogenesis and are consistent with in vivo characteristics of the microenvironment of the differentiated cells. Cytoskeletal-disrupting pharmacological agents modulate shape-based trends in lineage commitment verifying the critical role of focal adhesion and myosin-generated contractility during differentiation. Microarray analysis and pathway inhibition studies suggest that contractile cells promote osteogenesis by enhancing c-Jun N-terminal kinase (JNK) and extracellular related kinase (ERK1/2) activation in conjunction with elevated wingless-type (Wnt) signaling. Taken together, this work points to the role that geometric shape cues can play in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCs to appropriate fates.