Glycosaminoglycans modulate long-range mechanical communication between cells in collagen networks.
Glycosaminoglycans modulate long-range mechanical communication between cells in collagen networks.
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DOI：
10.1073/pnas.2116718119
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发表时间：
2022-04-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
糖胺聚糖(GAG)是在人体内普遍表达的碳水化合物，是影响天然组织发育、动态平衡和病理的关键大分子之一。在代谢紊乱、实体瘤和纤维组织中观察到GAG的异常积聚。在这里，我们从理论和实验上证明，由GAG的高极性性质引起的组织肿胀，通过改变胶原细胞外基质的组织和排列，显著影响驻留细胞之间的机械相互作用。GAG在调节细胞力传递中的作用可以指导再生医学中生物材料支架的设计，并为细胞间通讯在肿瘤进展和纤维化中的作用提供见解。细胞可以感知纤维细胞外基质(ECM)中的机械力并对其做出反应，距离比它们的大小要大得多。这种现象被称为长程力传递，是由于胶原纤维沿着拉力(压缩)方向的重新排列(弯曲)而实现的。然而，细胞外基质的其他关键结构成分，特别是糖胺多聚糖(GAG)是否可以影响细胞力传递的效率仍不清楚。在这里，我们建立了一个具有互穿缝隙的胶原网络中力传递的理论模型，该模型捕捉到了张力驱动的胶原纤维排列和由缝隙诱导的膨胀压力之间的竞争。利用这个模型，我们证明了GAG提供的膨胀压力通过以各向同性的方式拉伸纤维来增加胶原网络的硬度。我们发现，GAG诱导的膨胀压力可以帮助胶原纤维抵抗细胞施加收缩力量时的屈曲。这种机制阻碍了胶原纤维的排列，减少了远距离的细胞机械通讯。我们通过比较胶原凝胶和胶原蛋白-GAG凝胶上培养的细胞球体之间的胶原纤维排列强度，实验验证了理论预测。我们发现胶原蛋白-GAG凝胶中排列的胶原强度明显较低，这与GAG可以阻止胶原纤维排列的预测一致。这项工作中发现的GAG在调节力传递中的作用可以扩展到理解病理过程，如纤维化瘢痕的形成和癌症转移，在这些过程中，细胞在异常高浓度的GAG存在的情况下进行通信。
Glycosaminoglycans (GAGs) are carbohydrates that are expressed ubiquitously in the human body and are among the key macromolecules that influence the development, homeostasis, and pathology of native tissues. Abnormal accumulation of GAGs has been observed in metabolic disorders, solid tumors, and fibrotic tissues. Here we theoretically and experimentally show that tissue swelling caused by the highly polar nature of GAGs significantly affects the mechanical interactions between resident cells by altering the organization and alignment of the collagenous extracellular matrix. The role of GAGs in modulating cellular force transmission revealed here can guide the design of biomaterial scaffolds in regenerative medicine and provides insights on the role of cell–cell communication in tumor progression and fibrosis. Cells can sense and respond to mechanical forces in fibrous extracellular matrices (ECMs) over distances much greater than their size. This phenomenon, termed long-range force transmission, is enabled by the realignment (buckling) of collagen fibers along directions where the forces are tensile (compressive). However, whether other key structural components of the ECM, in particular glycosaminoglycans (GAGs), can affect the efficiency of cellular force transmission remains unclear. Here we developed a theoretical model of force transmission in collagen networks with interpenetrating GAGs, capturing the competition between tension-driven collagen fiber alignment and the swelling pressure induced by GAGs. Using this model, we show that the swelling pressure provided by GAGs increases the stiffness of the collagen network by stretching the fibers in an isotropic manner. We found that the GAG-induced swelling pressure can help collagen fibers resist buckling as the cells exert contractile forces. This mechanism impedes the alignment of collagen fibers and decreases long-range cellular mechanical communication. We experimentally validated the theoretical predictions by comparing the intensity of collagen fiber alignment between cellular spheroids cultured on collagen gels versus collagen–GAG cogels. We found significantly lower intensities of aligned collagen in collagen–GAG cogels, consistent with the prediction that GAGs can prevent collagen fiber alignment. The role of GAGs in modulating force transmission uncovered in this work can be extended to understand pathological processes such as the formation of fibrotic scars and cancer metastasis, where cells communicate in the presence of abnormally high concentrations of GAGs.
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影响因子：
8.6
作者：
Abouraddy, AF;Toussaint, KC
通讯作者：
Toussaint, KC
影响因子：
2.4
作者：
Lu, Xin L.;Wan, Leo Q.;Mow, Van C.
通讯作者：
Mow, Van C.
影响因子：
6.4
作者：
KOOCHEKPOUR, S;PILKINGTON, GJ;MERZAK, A
通讯作者：
MERZAK, A
影响因子：
4.6
作者：
Chen D;Smith LR;Khandekar G;Patel P;Yu CK;Zhang K;Chen CS;Han L;Wells RG
通讯作者：
Wells RG
DOI：
10.1073/pnas.1504258112
发表时间：
2015-08-04
影响因子：
11.1
作者：
Licup, Albert James;Muenster, Stefan;MacKintosh, Fred C.
通讯作者：
MacKintosh, Fred C.