Differential Regulation of Two- and Three-Dimensional Cell Function.

Abstract

The extracellular matrix (ECM) is a heterogeneous network of proteins, glycoproteins, and proteoglycans that not only scaffolds tissues but also acts as a central modulator of essential cell functions including proliferation, survival, and differentiation. Based on structure, ECMs can be classified as either two-dimensional (2-D) or three-dimensional (3-D). Consequently, cells assume a dimensional identity consistent with the ECM with which they interface. Epithelial and endothelial cells, which reside atop the sheet-like, planar basement membrane ECM, can be termed 2-D cells. Cells such as fibroblasts or adipocytes that are encased on all sides by fibrillar networks of interstitial collagens can be classified as 3-D cells. Recent evidence indicates that during development and disease, 2-D cells engage programs that promote acquisition of a 3-D dimensional identity and subsequent migration into the 3-D ECM – a process that can be termed the 2-D-to-3-D transition. Additionally, it has been demonstrated that ECM structure, composition, and dimensionality modulate the transcriptional programs and biochemical pathways that control cell function, with data indicating that distinct mechanisms of cell proliferation, migration, and differentiation are operative in 3-D compared to 2-D. We have identified an essential role for the zinc finger transcriptional repressor Snail1 in initiating the acquisition of a 3-D cell phenotype in 2-D cells during the pathogenesis of organ fibrosis, a disease characterized by widespread 2-D-to-3-D transition. Further, we have identified a previously unexpected function of Snail1 in overseeing the genetic programs that govern cell infiltration into interstitial tissue barriers following completion of 3-D differentiation in vitro and in vivo. Within 3-D ECMs, investigation of mechanisms underlying 3-D-specific regulation of cell function has uncovered a novel requirement for pericellular deposition of the glycoprotein fibronectin during capillary formation. Finally, we elucidate a novel paradigm by which structural and biophysical cues derived from cell-mediated remodeling of the local 3-D ECM are mechanically transmitted directly to the nuclear compartment to regulate tissue morphogenesis. These data provide novel insight into the differential modulation of 2-D and 3-D cell function and the interconversion of these dimensional phenotypes.