生物大分子在细胞内的扩散是生命活动的重要基础，在代谢、信号传导、分化以及物质运输等方面中起到关键作用。在过去三十多年的研究工作中，人们主要借助二维成像等方法来测量细胞内生物分子的扩散特征，并基于一个十分重要的假设，即细胞内的扩散为三维各向同性。然而，上述假设的真实性、以及细胞内的三维扩散动力学并不清楚。

近日，北京师范大学系统科学学院的李辉课题组与中科院物理研究所的王鹏业课题组合作，首次实验发现了细胞内的准二维扩散现象。该工作证明了细胞内的扩散并非各向同性，生物大分子更倾向于在xy二维平面内运动。同时，准二维扩散揭示了细胞内结构的异质性特征。

以上工作已发表在CPL Express Letters栏目

Quasi-Two-Dimensional Diffusion in Adherent Cells Revealed by Three-Dimensional Single Quantum Dot Tracking

Chao Jiang (江超), Bo Li (李波), Shuo-Xing Dou (窦硕星), Peng-Ye Wang (王鹏业), and Hui Li (李辉)

Chin. Phys. Lett. 2020, 37 (7): 078701

应编辑部邀请，北京师范大学陈晓松教授为本文作了点评！

Xiaosong Chen (陈晓松)

Chin. Phys. Lett. 2020, 37 (8): 080103

Starting from the never-ending agitated dance of pollen grains firstly discovered by Robert Brown in 1828, Brownian motion was known to represent the randomly diffusive movement of small particles in a simple solvent. Entering the twentieth century, milestone theories proposed by Albert Einstein, Marian Smoluchowski, and Paul Langevin attributed Brownian motion to the irregular thermal movements of liquid molecules, bridging the gap between the macro-scale particle motion and the micro-scale molecule fluctuations. In their pioneering works, the particle random displacements exhibit a Gaussian probability distribution with the mean square displacement (MSD) increasing linearly in time. Further experimental verification was shortly achieved by Perrin in 1909. Since then, the research on diffusion is unbroken both in experiment and theory, ranging from lifeless colloidal or polymeric solutions, to living biological systems.

In living cells, diffusion is crucial for molecule translocation in cytoplasm and mediates many important cellular processes. With the advanced single-molecule imaging technique, tracking individual molecules or tracer particles in living cells offers us opportunities to directly investigate the intracellular diffusion, and to effectively probe the intracellular crowding and microscopic cytoarchitectures. Different from Brownian motion, the anomalous diffusion, with a sublinear increase of MSD and a non-Gaussian distribution of displacement, was observed in cells. It was also revealed that the diffusion is driven by not only thermal fluctuations but also the actively fluctuating forces in cells. Although many studies have been made on intracellular diffusion in the past three decades, they were mainly carried out based on two-dimensional (2D) measurements, due to the lacking of sensitive instruments for measuring three-dimensional (3D) intracellular diffusion. In addition, an unverified assumption that the 3D diffusion in cells is isotropic is long-standing. However, the real 3D diffusion behavior of single molecules in cytoplasm as well as the 3D physical nature of cytoplasm are still unclear.

Recently, Jiang et al. discovered an anisotropical quasi-2D diffusion in cells by 3D single quantum dot (QD) tracking. They built a 3D single-particle tracking microscopy based on their previous 2D instrument, achieving the lateral 27-nm ( x - and y -directions) and axial 35-nm ( z -direction) spatial resolutions, and millisecond temporal resolution at the single-molecule level. By using QDs as the fluorescence tracers and loading individual QDs into the cytoplasm of human cancer cells, they for the first time discovered a quasi-2D diffusion in living cells, with the axial motion being severely confined. Disrupting several cellular organelles does not alter the quasi-2D diffusion pattern, suggesting that the quasi-2D diffusion is robust and may be attributed to the complex and planar structures in the adherent cells. This study thus has revealed the uncovered 3D anisotropic diffusion and heterogeneous cytoarchitectures in cells.

Another interesting suggestion in the work by Jiang et al. is that cells may utilize the cytoarchitecture to control the intracellular diffusion dynamics and regulate macromolecule transport. The quasi-2D diffusion could effectively promote the translocation and shorten the searching time of biological molecules in adherent cells, which is reminiscent of the cell migration: fast lateral translocation of actin monomers is coupled with the flat spreading morphology of lamellipodia.

With a broader perspective from 3D single-particle tracking, more investigations in cells are demanding to explore molecule behaviors, cytoarchitectures, and other physical natures in the real 3D intracellular world. These experiments would inspire related theoretical investigations of nonequilibrium complex systems. The interaction between experimental and theoretical studies in the future will reinforce our understanding about the diffusion inside living cells.

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