Nature Reviews Molecular Cell Biology最新文献

Receptors of insulin and insulin-like growth factors (IGFs) are receptor tyrosine kinases whose signalling controls multiple aspects of animal physiology throughout life. In addition to regulating metabolism and growth, insulin–IGF receptor signalling has recently been linked to a variety of new, cell type-specific functions. In the last century, key questions have focused on how structural differences of insulin and IGFs affect receptor activation, and how insulin–IGF receptor signalling translates into pleiotropic biological functions. Technological advances such as cryo-electron microscopy have provided a detailed understanding of how native and engineered ligands activate insulin–IGF receptors. In this Review, we highlight recent structural and functional insights into the activation of insulin–IGF receptors, and summarize new agonists and antagonists developed for intervening in the activation of insulin–IGF receptor signalling. Furthermore, we discuss recently identified regulatory mechanisms beyond ligand–receptor interactions and functions of insulin–IGF receptor signalling in diseases.

Adult stem cells balance self-renewal and differentiation to build, maintain and repair tissues. The role of signalling pathways and transcriptional networks in controlling stem cell function has been extensively studied, but there is increasing appreciation that mechanical forces also have a crucial regulatory role. Mechanical forces, signalling pathways and transcriptional networks must be coordinated across diverse length and timescales to maintain tissue homeostasis and function. Such coordination between stem cells and neighbouring cells dictates when cells divide, migrate and differentiate. Recent advances in measuring and manipulating the mechanical forces that act upon and are produced by stem cells are providing new insights into development and disease. In this Review, we discuss the mechanical forces involved when epithelial stem cells construct their microenvironment and what happens in cancer when stem cell niche mechanics are disrupted or dysregulated. As the skin has evolved to withstand the harsh mechanical pressures from the outside environment, we often use the stem cells of mammalian skin epithelium as a paradigm for adult stem cells shaping their surrounding tissues.

During development, endothelial cells (ECs) undergo an extraordinary specialization by which generic capillary microcirculatory networks spanning from arteries to veins transform into patterned organotypic zonated blood vessels. These capillary ECs become specialized to support the cellular and metabolic demands of each specific organ, including supplying tissue-specific angiocrine factors that orchestrate organ development, maintenance of organ-specific functions and regeneration of injured adult organs. Here, we illustrate the mechanisms by which microenvironmental signals emanating from non-vascular niche cells induce generic ECs to acquire specific inter-organ and intra-organ functional attributes. We describe how perivascular, parenchymal and immune cells dictate vascular heterogeneity and capillary zonation, and how this system is maintained through tissue-specific signalling activated by vasculogenic and angiogenic factors and deposition of matrix components. We also discuss how perturbation of organotypic vascular niche cues lead to erasure of EC signatures, contributing to the pathogenesis of disease processes. We also describe approaches that use reconstitution of tissue-specific signatures of ECs to promote regeneration of damaged organs.