Mechanoactive Tenogenic Differentiation of Human Mesenchymal Stem Cells
Mechanoactive Tenogenic Differentiation of Human Mesenchymal Stem Cells
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DOI：
10.1089/ten.tea.2006.0415
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发表时间：
2008-10-01
影响因子：
4.1
通讯作者：
Tuan, Rocky S.
中科院分区：
文献类型：
--
作者：
Kuo, Catherine K.;Tuan, Rocky S.
骨髓间充质干细胞(MSC)种植的胶原凝胶在静态或动态拉伸下是研究MSCs再生腱或韧带样组织的潜力的成熟模型。利用这一模型，已经证实了周期性拉伸机械刺激的反应上调了原纤维胶原mRNA的表达和蛋白质的产生。然而，推动MSC肌腱形成(分化为肌腱或韧带成纤维细胞)的机制尚未阐明。本研究通过动态三维组织工程模型研究周期性拉伸对基质生成和候选肌腱韧带标记物基因表达的影响，探讨人骨髓间充质干细胞肌腱形成的机制。3D MSC肌腱发生培养系统上调了硬化轴，但需要循环拉伸来维持这一假定的肌腱标志物的表达。细胞外基质染色显示肌腱新生组织的增强主要是由于动态负荷条件下基质沉积和重塑活性的变化，基质金属蛋白酶在转录水平上的差异调节，胶原mRNA水平的变化很小。周期刺激对Wnt基因表达的调节表明，Wnt4与Wnt5a在肌腱形成和软骨发育中的作用相似。这篇首次报道了在动态的三维组织工程模型中基质重塑和Wnt信号在人MSCs肌腱形成过程中的潜在参与，提供了对机械作用环境中肌腱形成机制的见解，并支持成人干细胞的治疗潜力。
A mesenchymal stem cell (MSC)-seeded collagen gel under static or dynamic tension is a well-established model to study the potential of MSCs in regenerating a tendon- or ligament-like tissue. Using this model, upregulation of fibrillar collagen mRNA expression and protein production has been demonstrated in response to cyclic tensile mechanical stimulation. However, the mechanisms driving MSC tenogenesis (differentiation into tendon or ligament fibroblasts) have not been elucidated. This study investigated the mechanisms of tenogenesis of human bone marrow-derived MSCs in a dynamic, three-dimensional (3D) tissue-engineering model by investigating the effects of cyclic stretching on matrix production and gene expression of candidate tendon and ligament markers. The 3D MSC tenogenesis culture system upregulated scleraxis, but cyclic stretching was required to maintain expression of this putative tendon marker over time. Enhanced tendinous neo-tissue development demonstrated with extracellular matrix staining was largely due to changes in matrix deposition and remodeling activity under dynamic loading conditions, as evidenced by differential regulation of matrix metalloproteinases at a transcriptional level with minimal changes in collagen mRNA levels. Regulation of Wnt gene expression with cyclic stimulation suggested a similar role for Wnt4 versus Wnt5a in tenogenesis as in cartilage development. This first report of the potential involvement of matrix remodeling and Wnt signaling during tenogenesis of human MSCs in a dynamic, 3D tissue-engineering model provides insights into the mechanisms of tenogenesis in a mechanoactive environment and supports the therapeutic potential of adult stem cells.