Hazenbiller Olesja, Nasr Saghar, Krawetz Roman J, Duncan Neil A
Biomedical Engineering Graduate Program, McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
Department of Mechanical and Manufacturing Engineering, Schulich School of Engineering, McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
J Orthop Res. 2018 Feb;36(2):799-807. doi: 10.1002/jor.23749. Epub 2017 Nov 20.
The use of embryonic stem cells (ESC) in regenerative medicine is restricted due to the possibility of tumorigenicity after inefficient or incomplete differentiation. Studies from our group, and others, suggest that mechanical stimuli may have a suppressive effect on the pluripotency/tumorigenesis of murine ESC (mESC). Furthermore, we have demonstrated that mESC seeded in a type I collagen scaffold, and transplanted into a murine bone fracture model, demonstrated repair without tumor formation. However, it remains unknown if mechanical factors were involved in blocking tumorigenicity of the mESC. Therefore, the aims of the current study were: (i) to characterize the mechanical environment within the transplanted construct (mESC-Col I) in an in vivo murine fracture model using computational analyses; and (ii) to reproduce this mechanical environment in vitro to elucidate the role of these mechanical factors on mESC pluripotent gene expression. It was predicted that the mESC-Col I construct was subjected to an average octahedral shear strain of ∼3.8% and a compressive strain of ∼3.1% within the fracture in vivo when the murine tibia was subjected to an axial compression load of 4 N (1 Hz). When a similar strain environment was replicated experimentally in vitro, the expression patterns of marker genes for pluripotency (Oct 4, Sox 2, Nanog, Rex 1, and oncogene ERas) were significantly down-regulated. This suggests that the local micro-mechanical environment within the fracture site in vivo may be involved in regulating stem cell fate after transplantation, and that these physical factors should be considered when developing regenerative medicine strategies. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:799-807, 2018.
由于在低效或不完全分化后存在致瘤可能性，胚胎干细胞（ESC）在再生医学中的应用受到限制。我们团队以及其他团队的研究表明，机械刺激可能对小鼠胚胎干细胞（mESC）的多能性/致瘤性具有抑制作用。此外，我们已经证明，接种在I型胶原支架中并移植到小鼠骨折模型中的mESC能够实现修复且不会形成肿瘤。然而，机械因素是否参与阻断mESC的致瘤性仍不清楚。因此，本研究的目的是：（i）使用计算分析来表征体内小鼠骨折模型中移植构建体（mESC-Col I）内的机械环境；（ii）在体外重现这种机械环境，以阐明这些机械因素对mESC多能基因表达的作用。据预测，当对小鼠胫骨施加4 N（1 Hz）的轴向压缩载荷时，mESC-Col I构建体在体内骨折部位会受到约3.8%的平均八面体剪应变和约3.1%的压缩应变。当在体外通过实验重现类似的应变环境时，多能性标记基因（Oct 4、Sox 2、Nanog、Rex 1和癌基因ERas）的表达模式显著下调。这表明体内骨折部位的局部微机械环境可能参与调节移植后干细胞的命运，并且在制定再生医学策略时应考虑这些物理因素。© 2017骨科研究协会。由Wiley Periodicals, Inc.出版。《矫形外科学研究》36:799 - 807, 2018。
