Department of Biomedical Engineering, Columbia University, City of New York, New York, USA.
Stem Cells. 2012 Nov;30(11):2561-70. doi: 10.1002/stem.1235.
Physical loading is a potent stimulus required to maintain bone homeostasis, partly through the renewal and osteogenic differentiation of mesenchymal stem cells (MSCs). However, the mechanism by which MSCs sense a biophysical force and translate that into a biochemical bone forming response (mechanotransduction) remains poorly understood. The primary cilium is a single sensory cellular extension, which has recently been shown to demonstrate a role in cellular mechanotransduction and MSC lineage commitment. In this study, we present evidence that short periods of mechanical stimulation in the form of oscillatory fluid flow (OFF) is sufficient to enhance osteogenic gene expression and proliferation of human MSCs (hMSCs). Furthermore, we demonstrate that the cilium mediates fluid flow mechanotransduction in hMSCs by maintaining OFF-induced increases in osteogenic gene expression and, surprisingly, to limit OFF-induced increases in proliferation. These data therefore demonstrate a pro-osteogenic mechanosensory role for the primary cilium, establishing a novel mechanotransduction mechanism in hMSCs. Based on these findings, the application of OFF may be a beneficial component of bioreactor-based strategies to form bone-like tissues suitable for regenerative medicine and also highlights the cilium as a potential therapeutic target for efforts to mimic loading with the aim of preventing bone loss during diseases such as osteoporosis. Furthermore, this study demonstrates a role for the cilium in controlling mechanically mediated increases in the proliferation of hMSCs, which parallels proposed models of polycystic kidney disease. Unraveling the mechanisms leading to rapid proliferation of mechanically stimulated MSCs with defective cilia could provide significant insights regarding ciliopathies and cystic diseases.
物理负荷是维持骨稳态所必需的有力刺激因素，部分原因是间充质干细胞（MSCs）的更新和成骨分化。然而，MSCs 如何感知生物物理力并将其转化为生化成骨反应（力学转导）的机制仍知之甚少。纤毛是一种单一的感觉细胞延伸，最近已显示其在细胞力学转导和 MSC 谱系分化中发挥作用。在这项研究中，我们提供了证据表明，以振荡液流（OFF）形式进行的短时间机械刺激足以增强人 MSCs（hMSCs）的成骨基因表达和增殖。此外，我们证明纤毛通过维持 OFF 诱导的成骨基因表达增加来介导 hMSCs 中的液流力学转导，并且令人惊讶的是，纤毛限制了 OFF 诱导的增殖增加。因此，这些数据表明初级纤毛在机械感受中具有促成骨作用，为 hMSCs 中的新型力学转导机制奠定了基础。基于这些发现，OFF 的应用可能是基于生物反应器的策略形成适合再生医学的骨样组织的有益组成部分，并且还突出了纤毛作为模仿加载的潜在治疗靶点的潜力，目的是预防骨质疏松症等疾病中的骨丢失。此外，这项研究表明纤毛在控制 hMSCs 机械介导的增殖增加中起作用，这与多囊肾病的模型一致。阐明具有缺陷纤毛的机械刺激 MSC 快速增殖的机制可能会为纤毛病和囊性疾病提供重要的见解。
