Dynamically Re‐Organized Collagen Fiber Bundles Transmit Mechanical Signals and Induce Strongly Correlated Cell Migration and Self‐Organization

Abstract

Correlated cell migration in fibrous extracellular matrix (ECM) is important in many biological processes. During migration, cells can remodel the ECM, leading to the formation of mesoscale structures such as fiber bundles. However,h ow such mesoscale structures regulate correlated single-cells migration remains to be elucidated. Here,u sing aq uasi-3D in vitro model, we investigate how collagen fiber bundles are dynamically re-organized and guide cell migration. By combining laser ablation technique with 3D tracking and active-particle simulations,w ed efinitively showt hat only the re-organized fiber bundles that carry significant tensile forces can guide strongly correlated cell migration, providing for the first time adirect experimental evidence supporting that matrix-transmitted long-range forces can regulate cell migration and self-organization. This force regulation mechanism can providen ew insights for studies on cellular dynamics, fabrication or selection of biomedical materials in tissue repairing, and many other biomedical applications.

Soft overcomes the hard: Flexible materials adapt to cell adhesion to promote cell mechanotransduction

“… Flexible materials Mechanism for promoting intracellular force Ref. a Soft fiber Reaction force increase [ 21 , [24] , [25] , [26] , [27] ] Soft rough hydrogel [ 37 ] Diffusible ligands Integrin clustering and Rac signaling activation [ [66] , [67] , [68] , [69] ] Stress relaxation hydrogel Integrin binding lifetime increase [ [41] , [42] , [43] ] Ligand spacing hydrogel [ 71 , 73 ] 2D degradable hydrogel [ 62 ] 3D degradable hydrogel Balancing space and stiffness [ 52 ] Stress-stiffening hydrogel [ 60 ] a Representative reference. …”

“…Elastin and collagen fibers usually provide stiffness, strength, extensibility and resilience to the tissue [ 19 , 20 ]. The fibrous structure of the natural ECM is often mimicked by biomaterials [ [21] , [22] , [23] ]. Compared with a highly crosslinked polymer chain in bulk hydrogels with the same components, the stiffness of a single fiber in fibrillar network is lower.…”

“…Baker et al have revealed cell-mediated aggregation of the fibrous matrix through actomyosin-generated force [ 26 ]. The deformed collagen fibers form bundles, which carry significant tensile forces to guide cell migration [ 27 ]. Matrix aggregation no longer occurs by inhibiting cell contractility.…”

Electro-assembly of a dynamically adaptive molten fibril state for collagen

“…In some cases, these hierarchical assemblies are connected through reversible interaction mechanisms to allow for structural reconfigurations and adaptive functional properties (3)(4)(5)(6). Examples include the dynamic cross-linking of collagen fibrils by sea cucumbers that allows them to reversibly tune their mechanics to evade predation (7)(8)(9), the dynamical reversible associations between collagen fibers and between fibers and cells that allow them to induce cell migration and self-organization to facilitate wound healing and remodeling (10)(11)(12), and the reversible associated collagen fibers in cephalopod's skin allow heterogeneous organization under the stretching of muscle fibers to provide a means of camouflage (13)(14)(15). In other cases, irreversible interactions are used to connect collagen assemblies to yield terminal structures that maintain homeostasis over time scales that can range from days to lifetimes.…”

Mechanical communication-induced cell directional migration and branching connections mediated by calcium channels, integrin β1 and N-cadherin

“…It has also been proved that cells can directly sense the mechanical force from the substrate besides conventional stiffness[26]. From computational simulation along with experimental verification, COL fiber bundles re-organized by cell contraction bear the major tensile force in the ECM, which can be transmitted to distant cells[27]. During migration of epithelial cell sheet, there is also long-range force transmission through cell-cell junctions, and ERK signal wave is activated in cells to promote the migration direction[13; 28].…”