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Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. They have important roles in numerous physiological and pathological processes, and show considerable promise as novel biomarkers of disease, as therapeutic agents and as drug delivery vehicles. Intriguingly, however, understanding of the cellular and molecular mechanisms that govern the many observed functions of EVs remains far from comprehensive, at least partly due to technical challenges in working with these small messengers. Here, we highlight areas of consensus as well as contentious issues in our understanding of the intracellular and intercellular journey of EVs: from biogenesis, release and dynamics in the extracellular space, to interaction with and uptake by recipient cells. We define knowledge gaps, identify key questions and challenges, and make recommendations on how to address these.Extracellular vesicles (EVs) mediate cell–cell communication in physiology and pathology but many questions remain about the mechanisms governing their delivery to recipient cells. This Expert Recommendation article highlights areas of progress and challenges in establishing the importance of EV-mediated communication in vivo.

Several different reactive oxygen species (ROS) are generated in vivo. They have roles in the development of certain human diseases whilst also performing physiological functions. ROS are counterbalanced by an antioxidant defence network, which functions to modulate ROS levels to allow their physiological roles whilst minimizing the oxidative damage they cause that can contribute to disease development. This Review describes the mechanisms of action of antioxidants synthesized in vivo, antioxidants derived from the human diet and synthetic antioxidants developed as therapeutic agents, with a focus on the gaps in our current knowledge and the approaches needed to close them. The Review also explores the reasons behind the successes and failures of antioxidants in treating or preventing human disease. Antioxidants may have special roles in the gastrointestinal tract, and many lifestyle features known to promote health (especially diet, exercise and the control of blood glucose and cholesterol levels) may be acting, at least in part, by antioxidant mechanisms. Certain reactive sulfur species may be important antioxidants but more accurate determinations of their concentrations in vivo are needed to help assess their contributions.Antioxidants modulate the levels of reactive oxygen species to allow their physiological roles whilst minimizing the oxidative damage and pathology. The roles and mechanisms of antioxidants are complex and context-dependent, necessitating better understanding of their actions in vivo and warranting caution with their use as therapeutic agents.

The field of extracellular vesicle (EV) research has developed rapidly over the last decade from the study of fundamental biology to a subject of significant clinical relevance. The potential of harnessing EVs in the diagnosis and treatment of diseases — including cancer and neurological and cardiovascular disorders — is now being recognized. Accordingly, the applications of EVs as therapeutic targets, biomarkers, novel drug delivery agents and standalone therapeutics are being actively explored. This Review provides a brief overview of the characteristics and physiological functions of the various classes of EV, focusing on their association with disease and emerging strategies for their therapeutic exploitation.The past decade has witnessed rapid growth in the field of extracellular vesicle (EV) research, and the potential of harnessing EVs in the treatment and diagnosis of diseases is now well recognized. Here, Cheng and Hill provide an overview of the physiological and pathological roles of EVs, discuss how they could be therapeutically exploited and consider the associated challenges.

Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.Cell death can result from the activation of dedicated programmed cell death machineries or disruption of pro-survival mechanisms. This Review describes the different major mechanisms of cell death and discusses recent insights into their relevance to disease.

The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.Dispensable, infected or neoplastic cells are removed by programmed cell death, including pathways for apoptosis, necroptosis and pyroptosis. Owing to differences in their mechanisms and physiological outcomes, these cell death pathways have traditionally been viewed as separate entities, but it has become clear that they are mechanistically and functionally connected.

COVID-19, caused by SARS-CoV-2, has recently affected over 1,200,000 people and killed more than 60,000. The key immune cell subsets change and their states during the course of COVID-19 remain unclear. We sought to comprehensively characterize the transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19 by single-cell RNA sequencing technique. It was found that T cells decreased remarkably, whereas monocytes increased in patients in the early recovery stage (ERS) of COVID-19. There was an increased ratio of classical CD14 ++ monocytes with high inflammatory gene expression as well as a greater abundance of CD14 ++ IL1β + monocytes in the ERS. CD4 + T cells and CD8 + T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naïve B cells decreased. Several novel B cell-receptor (BCR) changes were identified, such as IGHV3-23 and IGHV3-7, and isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development were confirmed. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity, which had not been reported yet. Furthermore, integrated analysis predicted that IL-1β and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2, and IL-4 may be beneficial for the recovery of COVID-19 patients. Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting COVID-19 patients are still vulnerable after hospital discharge. Identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19.

The term ‘fibroblast’ often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast–myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing.Fibroblasts undergo transient activation into myofibroblasts to restore homeostasis to injured tissues. This Review explores the influence of mechanical cues and epigenetic modifications on (myo)fibroblast activation and memory and discusses potential therapeutic prevention of persistent myofibroblast activation in fibrosis.

In the past decade, membraneless assemblies known as biomolecular condensates have been reported to play key roles in many cellular functions by compartmentalizing specific proteins and nucleic acids in subcellular environments with distinct properties. Furthermore, growing evidence supports the view that biomolecular condensates often form by phase separation, in which a single-phase system demixes into a two-phase system consisting of a condensed phase and a dilute phase of particular biomolecules. Emerging understanding of condensate function in normal and aberrant cellular states, and of the mechanisms of condensate formation, is providing new insights into human disease and revealing novel therapeutic opportunities. In this Perspective, we propose that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics (c-mods), and we discuss the strategies, techniques and challenges involved.Emerging understanding of biomolecular condensates — transient liquid-like droplets made up of proteins and nucleic acids — in normal and aberrant cellular states is providing new insights into human diseases. This Perspective proposes that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics, and discusses the strategies, techniques and challenges involved.

Two related papers show that cells disseminated from malignant lesions at early time points during tumorigenesis can contribute to metastases at distant organs and provide insights into the molecular basis of dissemination. A potential mechanism for metastases The origin of metastases in cancer remains an open question. In a pair of linked papers, Christoph Klein, Julio Aguirre-Ghiso and colleagues now show in mouse models that cells disseminated from tumours early in tumorigenesis can contribute to metastases at distant organs at such early time points. Both papers also provide insights into the molecular basis of dissemination, which may be useful as targets to prevent metastasis. Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant 1 . Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours 2 . However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases 3 , 4 , 5 . These findings, and those in pancreatic cancer 6 and melanoma 7 models, indicate that dissemination might occur during the early stages of tumour evolution 3 , 8 , 9 . However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown 8 . Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2 + p-p38 lo p-Atf2 lo Twist1 hi E-cad lo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2 + eDCC precursors invaded locally, intravasated and lodged in target organs. Her2 + eDCCs activated a Wnt-dependent epithelial–mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1 hi E-cad lo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase.