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The physiology and fate of living cells have long been known to be guided by their niche-specific microenvironments. Certain lineage-specific traits arise in mesenchymal stem cells from the elastic stiffness of the substratum on which they are cultured (1). This observation helped launch mechanobiology as a modern field, and has motivated a decade of research on how cells sense stiffness. A number of factors have been identified experimentally for transduction of mechanics to cells, including the local surface topology of the substratum to the cell through structural features, such as porosity (2). Mathematical models have determined that cells interact with the materials around them through dynamically cycling focal adhesions; this has led to an understanding of a molecular clutch that transmits forces and stabilizes larger focal adhesions on stiffer substrata (3, 4). These models have recently been extended to account for a broad range of detailed biophysical and kinetic phenomena within the cell, including intracellular transport and the spatial disposition of the cell, and have also accounted for nonlinearity of the extracellular material (5). The picture seemed fairly complete until focal adhesions were studied on a different type of substratum, a nonwoven mesh of nanofibers (6). Here, the same cells that consistently formed larger focal adhesions on stiffer substrata seemingly violated their rules. Does this apparent contradiction mean that cells follow different rules on fibrous substrata than they do on continuous substrata? Cao et al. (7) reveal in PNAS that there may indeed be a single set of rules that can explain both sets of results. The discovery that focal adhesions follow a single rulebook on fibrous …

The fibrous cellular microenvironment, and how cells make sense of a tangled web