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首页> 外文期刊>Tissue engineering, Part A >Purinergic Signaling Regulates the Transforming Growth Factor-beta 3-Induced Chondrogenic Response of Mesenchymal Stem Cells to Hydrostatic Pressure
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Purinergic Signaling Regulates the Transforming Growth Factor-beta 3-Induced Chondrogenic Response of Mesenchymal Stem Cells to Hydrostatic Pressure

机译：Purinergic信号调节间充质干细胞对静水压力的转化生长因子-β3诱导软骨形成反应。

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Although hydrostatic pressure (HP) is known to regulate chondrogenic differentiation of mesenchymal stromal/stem cells (MSCs), improved insight into the mechanotransduction of HP may form the basis for novel tissue engineering strategies. Previously, we demonstrated that matrix stiffness and calcium ion (Ca++) mobility regulate the mechanotransduction of HP; however, the mechanisms, by which these Ca++ signaling pathways are initiated, are currently unknown. The purinergic pathway, in which adenosine triphosphate (ATP) is released and activates P-receptors to initiate Ca++ signaling, plays a key role in the mechanotransduction of compression, but has yet to be investigated with regard to HP. Therefore, the objective of this study was to investigate the interplay between purinergic signaling, matrix stiffness, and the chondrogenic response of MSCs to HP. Porcine bone marrow-derived MSCs were seeded into soft or stiff agarose hydrogels and subjected to HP (10 MPa at 1Hz for 4 h/d for 21 days) or kept in free swelling conditions. Stiff constructs were incubated with pharmacological inhibitors of extracellular ATP, P2 receptors, or hemichannels, or without any inhibitors as a control. As with other loading modalities, HP significantly increased ATP release in the control group; however, inhibition of hemichannels completely abrogated this response. The increase in sulfated glycosaminoglycan (sGAG) synthesis and vimentin reorganization observed in the control group in response to HP was suppressed in the presence of all three inhibitors, suggesting that purinergic signaling is involved in the mechanoresponse of MSCs to HP. Interestingly, ATP was released from both soft and stiff hydrogels in response to HP, but HP only enhanced chondrogenesis in the stiff hydrogels, indicating that matrix stiffness may act downstream of purinergic signaling to regulate the mechanoresponse of MSCs to HP. Addition of exogenous ATP did not replicate the effects of HP on chondrogenesis, suggesting that mechanisms other than purinergic signaling also regulate the response of MSCs to HP.
机译：尽管静水压力（HP）已知调节间充质基质/干细胞（MSCs）的软骨分化，但对HP机械转导的深入了解可能构成新组织工程策略的基础。先前，我们证明了基质刚度和钙离子（Ca ++）迁移率可调节HP的机械传导。但是，目前尚不清楚启动这些Ca ++信号传导途径的机制。嘌呤能途径，其中释放三磷酸腺苷（ATP）并激活P受体以启动Ca ++信号传导，在压缩的机械转导中起关键作用，但尚未就HP进行研究。因此，本研究的目的是研究嘌呤能信号传导，基质刚度和MSC对HP的软骨形成反应之间的相互作用。将猪骨髓来源的MSCs接种到柔软或坚硬的琼脂糖水凝胶中，并进行HP（1Hz 10 MPa，4 h / d，持续21天）或保持在自由溶胀条件下。将刚性构建体与细胞外ATP，P2受体或半通道的药理抑制剂一起孵育，或将其与任何抑制剂一起作为对照。与其他加载方式一样，对照组的HP明显增加了ATP的释放;但是，抑制半通道完全废除了该反应。在所有三种抑制剂的存在下，对照组对HP的硫酸化糖胺聚糖（sGAG）合成和波形蛋白重组的增加在所有三种抑制剂的存在下均被抑制，表明嘌呤能信号参与了MSC对HP的机械反应。有趣的是，ATP响应于HP而从软性和硬性水凝胶中释放出来，但是HP仅增强了硬性水凝胶中的软骨形成，表明基质的硬度可能在嘌呤能信号的下游起作用，以调节MSC对HP的机械反应。外源性ATP的添加不能复制HP对软骨形成的作用，这表明除嘌呤能信号传导以外的其他机制也调节了MSC对HP的应答。

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