Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Berlin-Brandenburg Center and School for Regenerative Therapies, Berlin, Germany.
J Tissue Eng Regen Med. 2019 Nov;13(11):1992-2008. doi: 10.1002/term.2948. Epub 2019 Aug 13.
Mechanical boundary conditions critically influence the bone healing process. In this context, previous in vitro studies have demonstrated that cyclic mechanical compression alters migration and triggers osteogenesis of mesenchymal stromal cells (MSC), both processes being relevant to healing. However, it remains unclear whether this mechanosensitivity is a direct consequence of cyclic compression, an indirect effect of altered supply or a specific modulation of autocrine bone morphogenetic protein (BMP) signaling. Here, we investigate the influence of cyclic mechanical compression (ε = 5% and 10%, f = 1 Hz) on human bone marrow MSC (hBMSC) migration and osteogenic differentiation in a 3D biomaterial scaffold, an in vitro system mimicking the mechanical environment of the early bone healing phase. The open-porous architecture of the scaffold ensured sufficient supply even without cyclic compression, minimizing load-associated supply alterations. Furthermore, a large culture medium volume in relation to the cell number diminished autocrine signaling. Migration of hBMSCs was significantly downregulated under cyclic compression. Surprisingly, a decrease in migration was not associated with increased osteogenic differentiation of hBMSCs, as the expression of RUNX2 and osteocalcin decreased. In contrast, BMP2 expression was significantly upregulated. Enabling autocrine stimulation by increasing the cell-to-medium ratio in the bioreactor finally resulted in a significant upregulation of RUNX2 in response to cyclic compression, which could be reversed by rhNoggin treatment. The results indicate that osteogenesis is promoted by cyclic compression when cells condition their environment with BMP. Our findings highlight the importance of mutual interactions between mechanical forces and BMP signaling in controlling osteogenic differentiation.
力学边界条件对骨愈合过程有重要影响。在此背景下，先前的体外研究表明，循环机械压缩会改变间充质基质细胞（MSC）的迁移并触发其成骨作用，这两个过程都与愈合有关。然而，目前尚不清楚这种力敏感性是循环压缩的直接结果、供应改变的间接影响还是自分泌骨形态发生蛋白（BMP）信号的特定调节。在这里，我们研究了在 3D 生物材料支架中的循环机械压缩（ε=5%和 10%，f=1Hz）对人骨髓间充质基质细胞（hBMSC）迁移和成骨分化的影响，该体外系统模拟了早期骨愈合阶段的力学环境。支架的开-多孔结构确保了充足的供应，即使没有循环压缩，也最大限度地减少了与负载相关的供应改变。此外，与细胞数量相比，较大的培养基体积减少了自分泌信号。hBMSC 的迁移在循环压缩下显著下调。令人惊讶的是，迁移减少与 hBMSC 的成骨分化增加无关，因为 RUNX2 和骨钙素的表达减少。相反，BMP2 的表达显著上调。通过在生物反应器中增加细胞与培养基的比例来实现自分泌刺激，最终导致 RUNX2 对循环压缩的显著上调，rhNoggin 处理可逆转这种上调。结果表明，当细胞通过 BMP 调节其环境时，成骨作用会受到循环压缩的促进。我们的研究结果强调了机械力和 BMP 信号之间相互作用在控制成骨分化中的重要性。
