细胞在众多生理过程中感知、操纵和响应它们的机械微环境，然而，由于缺乏工具以定量推测复杂环境中动态细胞-细胞相互作用的错综复杂，我们对细胞如何传递、接收和解读环境信号与远离的细胞进行通信的理解严重有限。我们提出了一种计算方法，通过将细胞间的细胞外基质重塑波动与细胞间力传递关联起来（细胞-基质-细胞通信），系统地推测和量化长程细胞间力传递。我们展示了这些波动所含有的足够信息可以定义独特的特征，能够可靠地区分不同的细胞-细胞对。我们通过有限元模拟和生物活体三维成像结合纤维蛋白凝胶中成纤维细胞和癌细胞的实验，证明了我们的方法。以往的研究依赖于可见的纤维“带”在细胞之间形成来了解机械通信，然而我们的方法可以在从未形成可见带的情况下检测到机械传播。我们揭示了，虽然收缩能力是必要的，但带的形成对细胞-基质-细胞通信并非必需，而且即使细胞收缩能力大幅减小，机械信号仍能从一个细胞传播到另一个细胞。我们的方法为测量细胞间长程机械通信的基本特征提供了基础，并可能为基于高内容三维成像的筛选提供新的功能性输出。利用标准共聚焦显微镜推测细胞-基质-细胞通信的能力有着广泛应用和民主化的潜力。©2023 Springer Nature Limited.

Cells sense, manipulate and respond to their mechanical microenvironment in a plethora of physiological processes, yet the understanding of how cells transmit, receive and interpret environmental cues to communicate with distant cells is severely limited due to lack of tools to quantitatively infer the complex tangle of dynamic cell-cell interactions in complicated environments. We present a computational method to systematically infer and quantify long-range cell-cell force transmission through the extracellular matrix (cell-ECM-cell communication) by correlating ECM remodeling fluctuations in between communicating cells and demonstrating that these fluctuations contain sufficient information to define unique signatures that robustly distinguish between different pairs of communicating cells. We demonstrate our method with finite element simulations and live 3D imaging of fibroblasts and cancer cells embedded in fibrin gels. While previous studies relied on the formation of a visible fibrous 'band' extending between cells to inform on mechanical communication, our method detected mechanical propagation even in cases where visible bands never formed. We revealed that while contractility is required, band formation is not necessary, for cell-ECM-cell communication, and that mechanical signals propagate from one cell to another even upon massive reduction in their contractility. Our method sets the stage to measure the fundamental aspects of intercellular long-range mechanical communication in physiological contexts and may provide a new functional readout for high content 3D image-based screening. The ability to infer cell-ECM-cell communication using standard confocal microscopy holds the promise for wide use and democratizing the method.© 2023. Springer Nature Limited.