Visualization cell interaction with the extracellular matrix (ECM) mesh works plays a central role in understanding cell behavior and the corresponding regulatory mechanisms by the environment in vivo. However, long term visualization of 3D matrix structures remains challenging mainly due to photobleaching or blind spot in the currently available approaches. In this paper, we developed a label-free method based on light-sheet microcopy, termed light-sheet scattering microscopy (LSSM), as a satisfactory solution to solve this problem. LSSM can reliably determine structure of collagen matrices from different origin including bovine, human and rat tail. We verified that the quality and intensity of collagen structure images acquired by LSSM did not decline with time. LSSM offers abundant wavelength choice for matrix structure, maximizing combination possibilities for fluorescence to label the cells. LSSM can be used for visualizing ECM-cell interaction in 3D for long term and characterization of cell-applied forces. Interestingly, we observed ultrathin thread-like structures between cells and matrix using LSSM, which was not to be seen by normal fluorescence microscopy. In summary, LSSM provides a robust approach to investigate the complex interplay between cells and ECM in vitro under in vivo-mimicking conditions.

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