Biomedical materials: A restorative synthetic skin.

news & views limits cell spreading 5 , and prompts adhesion sites to align and provide signals that must be distinct from those received from a non-confined ligand 2. Cell collectives also sense open edges via the reduced impact of auto-inhibitory activity, such as the release of the cytokine TGF-β between cells 6 , or via the lack of cell–cell junctions mediated by cadherins or other adhesion systems towards the free edge 7. The relevance of the curvature — in addition to the influence of free edges — demonstrated by Kilian and co-authors implies that multiple, possibly additive variables are integrated in the cell, balancing decisions such as those leading to the development of stem-cell-like properties. As also shown by the authors, the cells sense curved-edge topologies through α 5 β 1 integrins (which bind fibronectin) and through mitogen-activated protein kinase (MAPK; which integrates multiple upstream signals from integrin and growth-factor receptors) signalling. Thus, geometry sensing overlaps, or integrates, with central-adhesion and growth-factor-receptor pathways involved in stemness regulation in normal and neoplastic cells 3,8. Stresses present at the edge may vary, depending on curvature, and support different types of focalized adhesions and their role in mediating different levels of actomyosin contractility and Rho/ROCK signalling, not unlike the machinery underlying cell sensing of substrate stiffness 1,8. Similarly, a confining edge could impose a 'jammed' state, in which cells undergo regulation of cell shape and reinforce cell–cell junctions towards one side, but lack the junction near the free edge 9. In addition, extracellular topologies may directly translate into membrane curvature and altered tension, which induce signalling to the actin cytoskeleton via F-BAR domain proteins 10. Thus, substrate geometry potentially controls cancer stem cell induction via an integrated programme comprising cell–matrix and cell–cell adhesions, as well as membrane curvature regulation and trafficking proteins. However, the specific mechanosensory mechanisms by which cells translate substrate curvature into differential signalling remain to be resolved. Such understanding is essential, since cells exposed to complex conditions in vivo are often mobile and encounter multiple topologies sequentially, thereby being likely to face tissue geometries that consolidate a malignant phenotype. Knowledge of how mechanosensory adhesion mechanisms and autocrine growth factor signalling cooperate may thus open new avenues for cancer therapy, such as targeting the curvature-sensing function therapeutically in order to revert stemness and to sensitize cancer cells to complementary treatments. Beyond cancer biology, deciphering how cells interpret the micro-and nanotopology …