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Early limb bud development has been of considerable interest for the study of embryological development and especially morphogenesis. The focus has long been on biochemical signalling and less on cell biomechanics and mechanobiology. However, their importance cannot be understated since tissue shape changes are ultimately controlled by active forces and bulk tissue rheological properties that in turn depend on cell–cell interactions as well as extracellular matrix composition. Moreover, the feedback between gene regulation and the biomechanical environment is still poorly understood. In recent years, novel experimental techniques and computational models have reinvigorated research on this biomechanical and mechanobiological side of embryological development. In this review, we consider three stages of early limb development, namely: outgrowth, elongation, and condensation. For each of these stages, we summarize basic biological regulation and examine the role of cellular and tissue mechanics in the morphogenetic process.

The origin of biological morphology and form is one of the deepest problems in science, underlying our understanding of development and the functioning of living systems. In 1952, Alan Turing showed that chemical morphogenesis could arise from a linear instability of a spatially uniform state, giving rise to periodic pattern formation in reaction–diffusion systems but only those with a rapidly diffusing inhibitor and a slowly diffusing activator. These conditions are disappointingly hard to achieve in nature, and the role of Turing instabilities in biological pattern formation has been called into question. Recently, the theory was extended to include noisy activator–inhibitor birth and death processes. Surprisingly, this stochastic Turing theory predicts the existence of patterns over a wide range of parameters, in particular with no severe requirement on the ratio of activator–inhibitor diffusion coefficients. To explore whether this mechanism is viable in practice, we have genetically engineered a synthetic bacterial population in which the signaling molecules form a stochastic activator–inhibitor system. The synthetic pattern-forming gene circuit destabilizes an initially homogenous lawn of genetically engineered bacteria, producing disordered patterns with tunable features on a spatial scale much larger than that of a single cell. Spatial correlations of the experimental patterns agree quantitatively with the signature predicted by theory. These results show that Turing-type pattern-forming mechanisms, if driven by stochasticity, can potentially underlie a broad range of biological patterns. These findings provide the groundwork for a unified picture of biological morphogenesis, arising from a combination of stochastic gene expression and dynamical instabilities.

We introduce an Active Vertex Model (AVM) for cell-resolution studies of the mechanics of confluent epithelial tissues consisting of tens of thousands of cells, with a level of detail inaccessible to similar methods. The AVM combines the Vertex Model for confluent epithelial tissues with active matter dynamics. This introduces a natural description of the cell motion and accounts for motion patterns observed on multiple scales. Furthermore, cell contacts are generated dynamically from positions of cell centres. This not only enables efficient numerical implementation, but provides a natural description of the T1 transition events responsible for local tissue rearrangements. The AVM also includes cell alignment, cell-specific mechanical properties, cell growth, division and apoptosis. In addition, the AVM introduces a flexible, dynamically changing boundary of the epithelial sheet allowing for studies of phenomena such as the fingering instability or wound healing. We illustrate these capabilities with a number of case studies.

Key Points Planar cell polarity (PCP) is a polarity axis that organizes cells in the plane of the tissue. PCP is conserved in metazoans and is essential for proper development and tissue homeostasis. Asymmetric and mutually exclusive subcellular enrichment of key PCP proteins patterns cells in planar-polarized tissues. PCP proteins also coordinate planar polarity between cells and control polarized behaviours by modulating the cytoskeleton. PCP patterns develop gradually from an initially disordered state through dynamic trafficking and various feedback interactions that can influence protein localization and stability. PCP patterns seem to be globally oriented along a pre-defined axis in a given tissue. Notably, multiple mechanistic inputs may have differential influences on PCP patterning depending on developmental timing and tissue context, and may only partially overlap in different contexts. The morphogenetic events governed by PCP signalling are best understood in Drosophila melanogaster , in which the particular orientation of hairs and bristles on the fly body has served to unravel basic principles of PCP-dependent processes. Information obtained from this model has helped to better understand equivalent mechanisms in vertebrates, particularly in the context of the orientation of fluid flow mediated by multiciliated cells and cell rearrangements during convergent extension. Mutations in PCP genes have been implicated in diverse human pathologies, and the body of evidence supporting the involvement of PCP aberrations in human birth defects continues to grow rapidly. Planar cell polarity — the asymmetric distribution of proteins in the plane of a cell sheet — dictates the orientation of various subcellular structures and drives collective cell rearrangements. Better understanding of this conserved axis of polarity can shed light on the mechanisms of morphogenetic processes and explain the underlying causes of human birth defects. Planar cell polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted WNT ligands and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.

Remodelling of the human embryo at implantation is indispensable for successful pregnancy. Yet it has remained mysterious because of the experimental hurdles that beset the study of this developmental phase. Here, we establish an in vitro system to culture human embryos through implantation stages in the absence of maternal tissues and reveal the key events of early human morphogenesis. These include segregation of the pluripotent embryonic and extra-embryonic lineages, and morphogenetic rearrangements leading to generation of a bilaminar disc, formation of a pro-amniotic cavity within the embryonic lineage, appearance of the prospective yolk sac, and trophoblast differentiation. Using human embryos and human pluripotent stem cells, we show that the reorganization of the embryonic lineage is mediated by cellular polarization leading to cavity formation. Together, our results indicate that the critical remodelling events at this stage of human development are embryo-autonomous, highlighting the remarkable and unanticipated self-organizing properties of human embryos. Zernicka-Goetz and colleagues report an in vitro culture system that recapitulates hallmarks of human embryo morphogenesis before gastrulation, including formation of the pro-amniotic cavity and appearance of the prospective yolk sac.

Mechanochemical processes in thin biological structures, such as the cellular cortex or epithelial sheets, play a key role during the morphogenesis of cells and tissues. In particular, they are responsible for the dynamical organization of active stresses that lead to flows and deformations of the material. Consequently, advective transport redistributes force-generating molecules and thereby contributes to a complex mechanochemical feedback loop. It has been shown in fixed geometries that this mechanism enables patterning, but the interplay of these processes with shape changes of the material remains to be explored. In this work, we study the fully self-organized shape dynamics using the theory of active fluids on deforming surfaces and develop a numerical approach to solve the corresponding force and torque balance equations. We describe the spontaneous generation of nontrivial surface shapes, shape oscillations, and directed surface flows that resemble peristaltic waves from self-organized, mechanochemical processes on the deforming surface. Our approach provides opportunities to explore the dynamics of self-organized active surfaces and can help to understand the role of shape as an integral element of the mechanochemical organization of morphogenetic processes.

SARS-CoV-2, a β-coronavirus, has rapidly spread across the world, highlighting its high transmissibility, but the underlying morphogenesis and pathogenesis remain poorly understood. Here, we characterize the replication dynamics, cell tropism and morphogenesis of SARS-CoV-2 in organotypic human airway epithelial (HAE) cultures. SARS-CoV-2 replicates efficiently and infects both ciliated and secretory cells in HAE cultures. In comparison, HCoV-NL63 replicates to lower titers and is only detected in ciliated cells. SARS-CoV-2 shows a similar morphogenetic process as other coronaviruses but causes plaque-like cytopathic effects in HAE cultures. Cell fusion, apoptosis, destruction of epithelium integrity, cilium shrinking and beaded changes are observed in the plaque regions. Taken together, our results provide important insights into SARS-CoV-2 cell tropism, replication and morphogenesis. Here, the authors characterize replication of SARS-CoV-2 in human airway epithelial (HAE) cultures and show that it can infect ciliated and secretory cells, affects transepithelial electrical resistance and causes plaque-like cytopathic effects associated with apoptosis.

Key Points Cells of the mononuclear phagocytic lineage differentiate into many different types of macrophage with a wide range of activities. These include specialized types of macrophage, such as Kupffer cells in the liver, microglial cells in the brain, dendritic cells and the highly specialized bone osteoclasts. Macrophages have many functions, including roles in immunity, apoptotic-cell clearance, wound healing and, as discussed in this Review, development. Analysis of macrophage-deficient mice has revealed many functions for these cells in development, and their loss perturbs the morphology and physiology of many tissues, such as the brain, mammary glands and bones. Macrophages promote epithelial-cell outgrowth and branching morphogenesis in several tissues, including the pancreas and the mammary glands. Macrophages regulate angiogenesis during development, wound repair and disease. Macrophages have a role in adipogenesis and obesity. Macrophages are strongly involved in many chronic diseases that are associated with ageing and provide trophic factors that are similar to those used during development; this has the effect of increasing disease pathology. Cancers sequester the developmental roles of macrophages to enhance their growth, invasive capacity, intravasation, progression and metastatic capacity. The homeostatic roles of macrophages in tissue development and maintenance are discussed, and insights are provided into how dysregulation of these primitive functions can be subverted in chronic diseases such as cancer and obesity to contribute to pathology. Specialized phagocytes are found in the most primitive multicellular organisms. Their roles in homeostasis and in distinguishing self from non-self have evolved with the complexity of organisms and their immune systems. Equally important, but often overlooked, are the roles of macrophages in tissue development. As discussed in this Review, these include functions in branching morphogenesis, neuronal patterning, angiogenesis, bone morphogenesis and the generation of adipose tissue. In each case, macrophage depletion impairs the formation of the tissue and compromises its function. I argue that in several diseases, the unrestrained acquisition of these developmental macrophage functions exacerbates pathology. For example, macrophages enhance tumour progression and metastasis by affecting tumour-cell migration and invasion, as well as angiogenesis.

Angiogenesis is a complex morphogenetic process whereby endothelial cells from existing vessels invade as multicellular sprouts to form new vessels. Here, we have engineered a unique organotypic model of angiogenic sprouting and neovessel formation that originates from preformed artificial vessels fully encapsulated within a 3D extracellular matrix. Using this model, we screened the effects of angiogenic factors and identified two distinct cocktails that promoted robust multicellular endothelial sprouting. The angiogenic sprouts in our system exhibited hallmark structural features of in vivo angiogenesis, including directed invasion of leading cells that developed filopodia-like protrusions characteristic of tip cells, following stalk cells exhibiting apical–basal polarity, and lumens and branches connecting back to the parent vessels. Ultimately, sprouts bridged between preformed channels and formed perfusable neovessels. Using this model, we investigated the effects of angiogenic inhibitors on sprouting morphogenesis. Interestingly, the ability of VEGF receptor 2 inhibition to antagonize filopodia formation in tip cells was context-dependent, suggesting a mechanism by which vessels might be able to toggle between VEGF-dependent and VEGF-independent modes of angiogenesis. Like VEGF, sphingosine-1-phosphate also seemed to exert its proangiogenic effects by stimulating directional filopodial extension, whereas matrix metalloproteinase inhibitors prevented sprout extension but had no impact on filopodial formation. Together, these results demonstrate an in vitro 3D biomimetic model that reconstitutes the morphogenetic steps of angiogenic sprouting and highlight the potential utility of the model to elucidate the molecular mechanisms that coordinate the complex series of events involved in neovascularization.

Tissue regeneration is a process that recapitulates and restores organ structure and function. Although previous studies have demonstrated wound-induced hair neogenesis (WIHN) in laboratory mice ( Mus ), the regeneration is limited to the center of the wound unlike those observed in African spiny ( Acomys ) mice. Tissue mechanics have been implicated as an integral part of tissue morphogenesis. Here, we use the WIHN model to investigate the mechanical and molecular responses of laboratory and African spiny mice, and report these models demonstrate opposing trends in spatiotemporal morphogenetic field formation with association to wound stiffness landscapes. Transcriptome analysis and K14-Cre-Twist1 transgenic mice show the Twist1 pathway acts as a mediator for both epidermal-dermal interactions and a competence factor for periodic patterning, differing from those used in development. We propose a Turing model based on tissue stiffness that supports a two-scale tissue mechanics process: (1) establishing a morphogenetic field within the wound bed (mm scale) and (2) symmetry breaking of the epidermis and forming periodically arranged hair primordia within the morphogenetic field (μm scale). Thus, we delineate distinct chemo-mechanical events in building a Turing morphogenesis-competent field during WIHN of laboratory and African spiny mice and identify its evo-devo advantages with perspectives for regenerative medicine. How hair follicle regeneration arises readily in some species ie. spiny rather than laboratory mice, is unclear. Here, authors compare them, showing an optimal stiffness is needed for placode formation and the difference in hair follicle regenerative behaviour after wounding is linked to Twist1.