Weakening of resistance force by cell–ECM interactions regulate cell migration directionality and pattern formation

Abstract

Collective migration of epithelial cells is a fundamental process in multicellular pattern formation. As they expand their territory, cells are exposed to various physical forces generated by cell–cell interactions and the surrounding microenvironment. While the physical stress applied by neighbouring cells has been well studied, little is known about how the niches that surround cells are spatio-temporally remodelled to regulate collective cell migration and pattern formation. Here, we analysed how the spatio-temporally remodelled extracellular matrix (ECM) alters the resistance force exerted on cells so that the cells can expand their territory. Multiple microfabrication techniques, optical tweezers, as well as mathematical models were employed to prove the simultaneous construction and breakage of ECM during cellular movement, and to show that this modification of the surrounding environment can guide cellular movement. Furthermore, by artificially remodelling the microenvironment, we showed that the directionality of collective cell migration, as well as the three-dimensional branch pattern formation of lung epithelial cells, can be controlled. Our results thus confirm that active remodelling of cellular microenvironment modulates the physical forces exerted on cells by the ECM, which contributes to the directionality of collective cell migration and consequently, pattern formation.

Improving Biological Functions of Three-Dimensional Printed Ti2448 Scaffolds by Decoration with Polydopamine and Extracellular Matrices

“…41 During migration, cells expand their region by remodeling the surrounding ECMs, which can facilitate other cells to migrate along the same path. 42 Our results also show that a large number of proteins, including fibronectin, are attached to Ti2448-PDA- ECM scaffolds (Figure 5d), which likely facilitate cell migration.…”

“…The migration of cells was achieved by the traction of the α5β1-integrin receptor from the cells on ECM components, including fibronectin, collagen I, and vitronectin. , ECMs can activate the intracellular signal cascade and provide mechanical and biochemical signals to resident cells . During migration, cells expand their region by remodeling the surrounding ECMs, which can facilitate other cells to migrate along the same path . Our results also show that a large number of proteins, including fibronectin, are attached to Ti2448-PDA-ECM scaffolds (Figure d), which likely facilitate cell migration.…”

Localization of multiple hydrogels with MultiCUBE platform spatially guides 3D tissue morphogenesis in vitro

“…Generally, Matrigel solution gelates into a soft gel at room temperature due to reversible noncovalent interactions among its constituent proteins 39,40 . However, the physical and mechanical conditions of Matrigel could be modified by adding genipin, a fruit-extract compound with low cellular toxicity, to form irreversible covalent bonds ( i.e., crosslink) among the constituent proteins ( Fig.5A ) 41,42 . This crosslinked Matrigel suppressed the branching development in NHBE tissues ( Fig.5B ), as indicated by extremely low apparent branch density and total branch length ( Fig.5C,D ).…”

“…However, the physical and mechanical conditions of Matrigel could be modified by adding genipin, a fruit-extract compound with low cellular toxicity, to form irreversible covalent bonds (i.e., crosslink) among the constituent proteins (Fig. 5A) 41,42 . This crosslinked Matrigel suppressed the branching development in NHBE tissues (Fig.…”

Eph/Ephrin-Based Protein Complexes: The Importance of cis Interactions in Guiding Cellular Processes

“…The ECM is a dynamic support that connects cells with each other through multiple components, mostly proteoglycans and fibrous proteins (i.e., collagen, laminin, elastin). Depending on its composition, ECM will have different elasticity and stiffness, which are factors known to contribute to cell commitment and differentiation ( Engler et al, 2006 ; Gilbert et al, 2010 ; Keung et al, 2011 ) as well as adhesion and migration ( Pathak and Kumar, 2012 ; Hagiwara et al, 2021 ). MMPs, together with metalloprotease-disintegrins (ADAMs), guide ECM remodeling and are therefore involved in cell adhesion and cell adhesion-dependent processes (i.e., migration, proliferation and differentiation, apoptosis, polarization, gene expression) in both homeostasis and cancer.…”