Current research interests

1. Visualizing molecular forces in living cells by a reversible shearing DNA-based tension probe  

Cells are highly dynamic in tissues, and their functions are constantly regulated by various forms of mechanical forces generated by the pushing, pulling and squeezing, both by other cells and the extracellular matrix (ECM). The mechanical forces generated by cells in tissues are substantial and can be easily in the range of many nN. Instead, the force per receptor is tiny, with its magnitude distributing from a few pN to tens of pN, but these molecular forces can precisely regulate the signal transduction process in time and space, thereby directly or indirectly controlling a number of biological responses such as cell differentiation, gene expression, and apoptosis. In the last decade, DNA-based tension sensors had made significant contributions to study the importance of mechanical forces in many biological systems. Albeit successful, one shortcoming of these techniques is their inaccessibility to reversibly measure receptor forces in a higher regime (i.e. >20-pN), which limited our understanding of the molecular details of mechano-chemo-transduction in living cells. We are developing a reversible shearing DNA-based tension probe (RSDTP) for probing molecular pN-scale forces between 4-60 pN transmitted by cells. Using these probes, we can easily distinguish the differences of force-bearing integrins without perturbing adhesion biology. We are particularly interested in understanding how cells sense and respond to mechanical forces at the molecular level.

      细胞在体内拥挤的环境中不仅通过挤来挤去以获得足够的生存空间,同时,细胞的生命过程也不断的受到挤压、拉伸、弯曲和拉扯细胞外基质(ECM)等过程产生的机械力所调控。尽管细胞上每个受体上传递的机械力小的令人难以置信---分布在几pN到几十pN范围,但是这些机械力信号可以深刻影响着胚胎发育、肿瘤迁移、免疫识别等多种过程。因此,在空间和时间上对细胞机械力进行精准地表征,将可以帮助我们深入认识细胞是如何利用微观力学信号诱导和改变相关的生物化学信号。在过去十年中,基于DNA的张力传感器为研究机械力在许多生物系统中的重要性做出了重大贡献。近十年来,基于分子力学传感器的力学可视化技术的提出,使得我们可以在分子水平上窥探细胞机械力传递过程和机制。但是,目前报道的多种分子力学传感器难以兼顾测量范围和可逆测量的需求,这限制了我们对细胞机械力信号传导的研究。我们实验室最近开发了一种基于新型DNA探针的细胞力学可视化技术,用于探测细胞传递的4-60pN之间的分子pN级力。使用这些探针,我们可以在不扰乱粘附生物学的情况下,很容易地分辨出受力的整合素的差异。我们对了解细胞如何在分子水平上感知和响应机械力特别感兴趣。

Reversible shearing DNA-based tension probe and cellular force images

Figure 1.png
Reference: Li et al, A Reversible shearing DNA probe for visualizing mechanically strong receptors in living cells, Nature Cell Biology, 2021. 
 https://www.nature.com/articles/s41556-021-00691-0.

Movie 1: Revealing the magnitude and spatial dynamics of integrin forces in living cells with RSDTP.

(Top, 17-pN; middle, 45-pN; bottom, 56-pN).

Movie 2: Imaging of different levels of integrin force in real time with multiplexed RSDTP.