Cell Migration on Suspended Fibers
Cell migration is a fundamental process necessary for the creation of tissues during embryogenesis, immune surveillance, wound repair, inflammation, and the invasion and metastasis of cancer cells. All of these processes occur in the context of the extracellular matrix. For decades, there has been a concerted effort to understand the basic mechanisms of cell migration and other cellular behaviors, focused largely on cells cultured on 2D surfaces. Studies in vivo demonstrate that cells also use migratory approaches different than those observed on 2D surfaces in vitro, and even 2D migration in vivo occurs in the context of 3D tissue. Recently, there has been a move to apply the wealth of knowledge regarding what we know about 2D cell migration to understand cell migration within the context of 3D matrices and in vivo. Leaders in the field have identified several challenges to this task, which include the fact that migration in 3D matrices in vivo is quite different from 2D matrices, the difficulty creating relevant in vitro matrices that capture matrix composition and topography of in vivo microenvironments, and the challenges of manipulating the environment in vivo”.
- Patti Keely (2015)
At STEP Lab, we deconstruct the effects of the various physical characteristics of the ECM on single and collective cell migration in precisely controlled environments. Through design of suspended fiber networks of varying attributes, we have demonstrated the following migratory responses:
Crosshatch nanofiber networks of tunable interfiber spacing induce plasticity in cell migration and cytoskeletal response
Biomechanical cues within tissue microenvironments are critical for maintaining homeostasis, and their disruption can contribute to malignant transformation and metastasis. Once transformed, metastatic cancer cells can migrate persistently by adapting(plasticity) to changes in the local fibrous extracellular matrix, and current strategies to recapitulate persistent migration rely exclusively on the use of aligned geometries. Here, the controlled interfiber spacing in suspended crosshatch networks of nanofibers induces cells to exhibit plasticity in migratory behavior (persistent and random) and the associated cytoskeletal arrangement. At dense spacing (3 and 6 mm), unexpectedly, elongated cells migrate persistently (in 1 dimension) at high speeds in 3-dimensional shapes with thick nuclei, and short focal adhesion cluster (FAC) lengths. With increased spacing (18 and 36 mm), cells attain 2-dimensional morphologies, have flattened nuclei and longer FACs, and migrate randomly by rapidly detaching their trailing edges that strain the nuclei by∼35%.At 54-mmspacing, kite-shaped cells become near stationary. Poorly developed filamentous actin stress fibers are found only in cells on 3-mm networks. Gene-expression profiling shows a decrease in transcriptional potential and a differential up-regulation of metabolic pathways. The consistency in observed phenotypes across cell lines supports using this platform to dissect hallmarks of plasticity in migration in vitro