On July 12, 2022, Nature Materials, a top international academic journal, published the research results of the joint research team of Xi’an Jiaotong University, Finnish Tuku University, university of Minnesota, Washington University of St. Louis, Nanjing University of Aeronautics and Astronautics entitled “Directed cell migration toward softer environments” online.
The research team found that U-251MG glioma cells and nerve cell axon terminal growth cones have obvious “negative durotaxis” behavior, revealing the mechanobiological mechanism of different types of cells sensing and responding to differences in the mechanical properties of the extracellular matrix.
Cheng Bo, assistant professor of the Institute of Biomimetic Engineering and Biomechanics, School of Life Sciences, Xi’an Jiaotong University, is the co-first author, Professor Lin Min of Xi’an Jiaotong University, Professor Johanna Ivaska of Finnish Tuku University, Professor Mark Distefano and Professor David Odde of the University of Minnesota are the corresponding authors of the paper.
Cells in vivo are always subjected to multiple forms of mechanical stimulation (such as extracellular matrix mechanical properties, fluid shear force, matrix stretching, etc.). Cells can sense these mechanical stimuli and transduce the mechanical stimulus signals into biochemical signals, thereby activating a series of responses within the cell, ultimately affecting the functions of cell differentiation and migration. The mechanical properties of the extracellular matrix ( such as stiffness gradients ) play an important role in the growth and development of organisms and the occurrence and development of diseases. For example, during the development of cancer, the fibrosis of the diseased tissue leads to a change in the extracellular matrix stiffness gradient, which in turn affects the aggressive behavior of cancer cells; During nervous system growth, development, and regeneration, the stiffness gradient of the matrix is the main driver of axonal tendentious growth of nerve cells. Therefore, studying how cells respond to matrix stiffness gradients and their underlying molecular mechanisms is one of the most urgent scientific problems in biology, biomedicine, and biomechanics.
Numerous studies have confirmed that cells cultured on a rigid gradient matrix (e.g., fibroblasts, breast cancer cells) tend to migrate towards a hard matrix, often referred to as “Durotaxis.” Recently, Xi’an Jiaotong University, Finland Tuku University, university of Minnesota, Washington University st. Louis, Nanjing University of Aeronautics and Astronautics and other units cooperated to find that U-251MG glioma cells and nerve cell axon terminal growth cones have obvious “negative durotaxis” behavior (Figure 1). The research team found that the results of molecular biology experiments on related key proteins were difficult to reveal the above abnormal cell migration phenomena. To this end, based on the principle of mechanical equilibrium, the research team established a mechanical model of cell migration based on the adhesion strengthening effect of integrins, and proposed that the ankle protein (talin) domain attached to it and in the folded state is forced to be opened during the process of integrin stress, and then recruit vinculin, realize the force-sensitive adhesion strengthening process, and eventually lead to the “hardening” migration of cells; The absence of a force-sensitive adhesion reinforcement effect leads to “negative hardening” migration of cells. The predictions of the above mechanical model have been verified experimentally: through the knockdown experiment of ankle protein, breast cancer cells with “hardening” migration behavior produce “negative hardening” migration phenomenon.
Figure 1: Cell “negative-durotaxis” migration phenomenon. (A-B) experimental observations show that glioma cells tend to migrate to a softer matrix; (C-E) Established a mechanical model of cell migration based on integrin adhesion enhancement effect and reproduced the experimental results, revealing that the absence of integrin adhesion reinforcement mediated by changes in ankle protein force conformation plays a key role in cell “negative hardening” migration. (F) Experimental knockdown of ankle protein to validate the theoretical model.
This study provides a unified theoretical explanation for the migration mechanism of “hardening” and “negative hardening” of cancer cells from the perspective of the interaction of ankle protein force conformation changes mediated by integrin adhesion enhancement (Figure 2). This research work reveals the molecular mechanism of different types of cells that perceive and respond to differences in the mechanical characteristics of extracellular matrix, which provides a theoretical basis for exploring the mechanism of disease occurrence and development.
Figure 2: Biomechanical mechanisms based on “hardening” and “negative hardening” migration of adhesion-enhanced (missing) effector cells.
The research was also supported by Professor Lu Tianjian of Nanjing University of Aeronautics and Astronautics, Professor Xu Feng of Xi’an Jiaotong University, and Professor Guy Genin of Washington University st. Louis. This work has been funded by the National Natural Science Foundation of China, the Shaanxi Provincial Young Top Talents Support Program and the Xi’an Jiaotong University Young Top Talents Support Program.
Professor Lin Min’s research group focused on the scientific problem of the mechanobiological mechanism of cell function regulation mediated by cellular force-sensitive receptors, through the construction and characterization of the cell mechanics microenvironment, combined with mechanical models and cell biology experiments, carried out a series of studies, and carried out original work in the field of cell biomechanics. 2021), Science Advances (2020) and other authoritative journals. (Source: Science Network)
Related paper information:https://doi.org/10.1038/s41563-022-01294-2