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Key Points The process of contact inhibition of locomotion (CIL) has been observed in a wide range of migrating cell types in vitro . CIL encompasses a range of different overall behaviours, from simple cessation of migration to complete repolarization; however, it is likely that common regulatory mechanisms exist among these behaviours. A prototypical CIL response involves a series of distinct stages, including cell–cell adhesion, modulation of cytoskeletal dynamics and finally cell repolarization. These steps are regulated by mechano-chemical signals, which must be integrated to induce a seamless response. Numerous mathematical models that incorporate CIL have revealed that it can lead to emergent cellular behaviours, from cell patterning to collective motion. Since the 1950s, CIL has primarily been studied in vitro . However, recent work revealed its requirement during several developmental processes, such as neuronal cell dispersion, macrophage distribution and the collective migration of neural crest cells. CIL and its regulation are likely to be important for many other physiological processes and has been implicated in pathologies such as cancer metastasis. Contact inhibition of locomotion (CIL) involves collisions with other cells during cell migration that typically induce cessation of movement or a change of migratory direction. A molecular description of CIL and details of its involvement in various cellular processes are emerging, demonstrating that CIL is a highly heterogeneous response with important functions in vivo . Contact inhibition of locomotion (CIL) is a process whereby a cell ceases motility or changes its trajectory upon collision with another cell. CIL was initially characterized more than half a century ago and became a widely studied model system to understand how cells migrate and dynamically interact. Although CIL fell from interest for several decades, the scientific community has recently rediscovered this process. We are now beginning to understand the precise steps of this complex behaviour and to elucidate its regulatory components, including receptors, polarity proteins and cytoskeletal elements. Furthermore, this process is no longer just in vitro phenomenology; we now know from several different in vivo models that CIL is essential for embryogenesis and in governing behaviours such as cell dispersion, boundary formation and collective cell migration. In addition, changes in CIL responses have been associated with other physiological processes, such as cancer cell dissemination during metastasis.

Collective alignment of cell populations is a commonly observed phenomena in biology. An important example are aligning fibroblasts in healthy or scar tissue. In this work we derive and simulate a mechanistic agent-based model of the collective behaviour of actively moving and interacting cells, with a focus on understanding collective alignment. The derivation strategy is based on energy minimisation. The model ingredients are motivated by data on the behaviour of different populations of aligning fibroblasts and include: Self-propulsion, overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces. We find that there is an optimal ratio of self-propulsion speed and overlap avoidance that maximises collective alignment. Further we find that deformability aids alignment, and that cell-cell junctions by themselves hinder alignment. However, if cytoskeletal forces are transmitted via cell-cell junctions we observe strong collective alignment over large spatial scales.

Cell migration is hypothesized to involve a cycle of behaviours beginning with leading edge extension. However, recent evidence suggests that the leading edge may be dispensable for migration, raising the question of what actually controls cell directionality. Here, we exploit the embryonic migration of Drosophila macrophages to bridge the different temporal scales of the behaviours controlling motility. This approach reveals that edge fluctuations during random motility are not persistent and are weakly correlated with motion. In contrast, flow of the actin network behind the leading edge is highly persistent. Quantification of actin flow structure during migration reveals a stable organization and asymmetry in the cell-wide flowfield that strongly correlates with cell directionality. This organization is regulated by a gradient of actin network compression and destruction, which is controlled by myosin contraction and cofilin-mediated disassembly. It is this stable actin-flow polarity, which integrates rapid fluctuations of the leading edge, that controls inherent cellular persistence. Yolland et al. demonstrate persistent flow of the actin flow behind the leading edge and its impact on cell directionality during migration.

The healing of a skin wound is a complex process involving many cell lineages. In adult tissues, repair is always accompanied by a robust inflammatory response, which is necessary to counter the potential for infection at any site where the skin barrier is breached. Unlike embryonic tissues that can repair perfectly without a remnant scar at the wound site, adult tissue repair always leads to formation of a fibrotic scar where the wound has healed. In recent years, it has become clear that the wound inflammatory response may be, at least in part, responsible for fibrosis at sites of tissue repair. In this review, we consider the beneficial vs the detrimental functions of inflammatory cells during the repair response and compare data from other tissues, the lung, and liver, where fibrosis and its resolution may be related to a damage-triggered inflammatory response. We also consider how it may be possible to molecularly disentangle the potentially good from the bad influences of inflammatory cells during tissue repair and how fundamental studies in inflammatory cell biology may prove the way forward for development of drug targets in this respect.

Cells are thought to adopt mechanistically distinct migration modes depending on cell-type and environmental factors. These modes are assumed to be driven by mutually exclusive actin cytoskeletal organizations, which are either lamellar (flat, branched network) or cortical (crosslinked to the plasma membrane). Here we exploit Drosophila macrophage (hemocyte) developmental dispersal to reveal that these cells maintain both a lamellar actin network at their cell front and a cortical actin network at the rear. Loss of classical actin cortex regulators, such as Moesin, perturb hemocyte morphology and cell migration. Furthermore, cortical and lamellipodial actin networks are interregulated. Upon phosphorylation and binding to the plasma membrane, Moesin is advected to the rear by lamellar actin flow. Simultaneously, the cortical actin network feeds back on the lamella to help regulate actin flow speed and leading-edge dynamics. These data reveal that hemocyte motility requires both lamellipodial and cortical actin architectures in homeostatic equilibrium. Actin in migrating cells adopt distinct geometries depending on the migration mode. Using a probe to highlight membrane-bound actin, the authors reveal that fly macrophages require coordination of lamellar and cortical actin networks during motility.

Cell migration is important for development and its aberrant regulation contributes to many diseases. The Scar/WAVE complex is essential for Arp2/3 mediated lamellipodia formation during mesenchymal cell migration and several coinciding signals activate it. However, so far, no direct negative regulators are known. Here we identify Nance-Horan Syndrome-like 1 protein (NHSL1) as a direct binding partner of the Scar/WAVE complex, which co-localise at protruding lamellipodia. This interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. Furthermore, active Rac binds to NHSL1 at two regions that mediate leading edge targeting of NHSL1. Surprisingly, NHSL1 inhibits cell migration through its interaction with the Scar/WAVE complex. Mechanistically, NHSL1 may reduce cell migration efficiency by impeding Arp2/3 activity, as measured in cells using a Arp2/3 FRET-FLIM biosensor, resulting in reduced F-actin density of lamellipodia, and consequently impairing the stability of lamellipodia protrusions. Cell migration is essential for many physiological processes. Its deregulation causes cancer metastasis and it is not well understood how it is tightly controlled. We identify NHSL1 as a negative regulator of actin nucleating Scar/WAVE-Arp2/3 complexes, cell protrusion stability, and cell migration.

Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via ATG2 repression. In Drosophila infected with Mycobacterium marinum , mycobacterium-induced STAT activity triggered by unpaired -family cytokines reduces Atg2 expression, permitting deregulation of lipid droplets. Increased Atg2 expression or reduced macrophage triglyceride biosynthesis, normalizes lipid deposition in infected phagocytes and reduces numbers of viable intracellular mycobacteria. In human macrophages, addition of IL-6 promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2 regulation as a mechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infection in Drosophila . Cytokines and their associated pathways can affect survival of Mycobacterium tuberculosis in macrophages, representing potential targets for host-directed therapies. Here, Péan et al . show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplet homeostasis.

The cell/microenvironment interface is the starting point of integrin-mediated mechanotransduction, but many details of mechanotransductive signal integration remain elusive due to the complexity of the involved (extra)cellular structures, such as the glycocalyx. We used nano-bio-interfaces reproducing the complex nanotopographical features of the extracellular matrix to analyse the glycocalyx impact on PC12 cell mechanosensing at the nanoscale ( e.g. , by force spectroscopy with functionalised probes). Our data demonstrates that the glycocalyx configuration affects spatio-temporal nanotopography-sensitive mechanotransductive events at the cell/microenvironment interface. Opposing effects of major glycocalyx removal were observed, when comparing flat and specific nanotopographical conditions. The excessive retrograde actin flow speed and force loading are strongly reduced on certain nanotopographies upon strong reduction of the native glycocalyx, while on the flat substrate we observe the opposite trend. Our results highlight the importance of the glycocalyx configuration in a molecular clutch force loading-dependent cellular mechanism for mechanosensing of microenvironmental nanotopographical features. Graphical Abstract

L-selectin is a cell adhesion molecule that tethers free-flowing leukocytes from the blood to luminal vessel walls, facilitating the initial stages of their emigration from the circulation toward an extravascular inflammatory insult. Following shear-resistant adhesion to the vessel wall, L-selectin has frequently been reported to be rapidly cleaved from the plasma membrane (known as ectodomain shedding), with little knowledge of the timing or functional consequence of this event. Using advanced imaging techniques, we observe L-selectin shedding occurring exclusively as primary human monocytes actively engage in transendothelial migration (TEM). Moreover, the shedding was localized to transmigrating pseudopods within the subendothelial space. By capturing monocytes in midtransmigration, we could monitor the subcellular distribution of L-selectin and better understand how ectodomain shedding might contribute to TEM. Mechanistically, L-selectin loses associationwith calmodulin (CaM; a negative regulator of shedding) specifically within transmigrating pseudopods. In contrast, L-selectin/CaM interaction remained intact in nontransmigrated regions of monocytes. We show phosphorylation of L-selectin at Ser 364 is critical for CaM dissociation, which is also restricted to the transmigrating pseudopod. Pharmacological or genetic inhibition of L-selectin shedding significantly increased pseudopodial extensions in transmigrating monocytes, which potentiated invasive behavior during TEM and prevented the establishment of front/back polarity for directional migration persistence once TEM was complete. We conclude that L-selectin shedding directly regulates polarity in transmigrated monocytes, which affirms an active role for this molecule in driving later stages of the multistep adhesion cascade.

Tissue repair in embryos is rapid, efficient and perfect and does not leave a scar, an ability that is lost as development proceeds. Wheras adult wound keratinocytes crawl forwards over the exposed substratum to close the gap, a wound in the embryonic epidermis is closed by contraction of a rapidly assembled actin purse string. Blocking assembly of this cable in chick and mouse embryos, by drugs or by inactivation of the small GTPase Rho, severely hinders the re-epithelialization process. Live studies of epithelial repair in GFP-actin-expressing Drosophila embryos reveal actin-rich filopodia associated with the cable, and although these protrusions from leading edge cells appear to play little role in epithelial migration, they are essential for final zippering of the wound edges together-inactivation of Cdc42 prevents their assembly and blocks the final adhesion step. This wound re-epithelialization machinery appears to recapitulate that used during naturally occurring morphogenetic episodes as typified by Drosophila dorsal closure. One key difference between embryonic and adult repair, which may explain why one heals perfectly and the other scars, is the presence of an inflammatory response at sites of adult repair where there is none in the embryo. Our studies of repair in the PU.1 null mouse, which is genetically incapable of raising an inflammatory response, show that inflammation may indeed be partly responsible for scarring, and our genetic studies of inflammation in zebrafish (Danio rerio) larvae suggest routes to identifying gene targets for therapeutically modulating the recruitment of inflammatory cells and thus improving adult healing.