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Cell competition arises in heterogeneous tissues when neighbouring cells sense their relative fitness and undergo selection. It has been a challenge to define contexts in which cell competition is a physiologically relevant phenomenon and to understand the cellular features that underlie fitness and fitness sensing. Drawing on examples across a range of contexts and length scales, we illuminate molecular and cellular features that could underlie fitness in diverse tissue types and processes to promote and reinforce long-term maintenance of tissue function. We propose that by broadening the scope of how fitness is defined and the circumstances in which cell competition can occur, the field can unlock the potential of cell competition as a lens through which heterogeneity and its role in the fundamental principles of complex tissue organisation can be understood., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

The transcriptional coactivator Yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) induces cell proliferation through nuclear localization at low cell density. Conversely, at extremely high cell density, the Hippo pathway, which regulates YAP/TAZ, is activated. This activation leads to the translocation of YAP/TAZ into the cytoplasm, resulting in cell cycle arrest. Various cancer cells have several times more YAP/TAZ than normal cells. However, it is not entirely clear whether this several-fold increase in YAP/TAZ alone is sufficient to overcome proliferation inhibition (contact inhibition) under high-density conditions, thereby allowing continuous proliferation. In this study, we construct a three-dimensional (3D) mathematical model of cell proliferation incorporating the Hippo-YAP/TAZ pathway. Herein, a significant innovation in our approach is the introduction of a novel modeling component that inputs cell density, which reflects cell dynamics, into the Hippo pathway and enables the simulation of cell proliferation as the output response. We assume such 3D model with cell-cell interactions by solving reaction and molecular dynamics (MD) equations by applying adhesion and repulsive forces that act between cells and frictional forces acting on each cell. We assume Lennard-Jones (12-6) potential with a softcore character so that each cell secures its exclusive domain. We set cell cycles composed of mitotic and cell growth phases in which cells divide and grow under the influence of cell kinetics. We perform mathematical simulations at various YAP/TAZ levels to investigate the extent of YAP/TAZ increase required for sustained proliferation at high density. The results show that a twofold increase in YAP/TAZ levels of cancer cells was sufficient to evade cell cycle arrest compared to normal cells, enabling cells to continue proliferating even under high-density conditions. Finally, this mathematical model, which incorporates cell-cell interactions and the Hippo-YAP/TAZ pathway, may be applicable for evaluating cancer malignancy based on YAP/TAZ levels, developing drugs to suppress the abnormal proliferation of cancer cells, and determining appropriate drug dosages. The source codes are freely available., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Umegaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Pericyte-to-pericyte communication via interpericyte tunneling nanotubes (IP-TNTs) is an important mechanism by which spatial and temporal precision in neurovascular coupling is achieved. This study quantifies the distribution and morphologic characteristics of IP-TNTs in the normal human macula., Methods: Ultra high-resolution, three-dimensional microscopic imaging of 11 perfusion-labeled normal human donor eyes was performed. Immunofluorescent markers for collagen IV, glial fibrillary acidic protein, nuclei, α-smooth muscle actin and phalloidin were used to distinguish IP-TNTs from perfused/nonperfused capillaries and glia processes. IP-TNT length, diameter and density in each capillary plexus was quantified and compared., Results: IP-TNTs were present in all capillary plexuses. IP-TNTs bridged capillary segments within and between capillary plexuses but did not connect capillaries to arterioles or venules. Mean length of IP-TNTs was 72.6 ± 39.5µm (range 14.0 to 202 µm) and mean diameter was 1.0 ± 0.42µm. IP-TNT length was non-normally distributed with a right-skewed distribution and 43% were 'short' (<55µm). Diameters were greater in the "long" (1.13 ± 0.44 µm) than "short" (0.82 ± 0.33 µm; P < 0.001) IP-TNTs. Density of IP-TNTs was greater in the superficial vascular plexus (3.80 ± 0.69 per 500 µm2) compared to the intermediate (1.85 ± 0.80 per 500 µm2; P < 0. 0001) and deep capillary plexus (1.58 ± 0.84 per 500 µm2; P < 0.0001). No significant difference in IP-TNT density was found between the four macula quadrants (P = 0.98)., Conclusions: The distribution of IP-TNTs in the human macula is non-uniform and is associated with the compartmentalized nature of retinal energy consumption and microvascular perfusion. The nonuniform properties of IP-TNTs may predispose distinct vascular beds to injury in conditions such as diabetes.

Malignant tumors are complicated structures of cancer cells that are constantly in communication with their local and distant environment. Exosomes are released by tumor cells and can facilitate the cell-cell interaction within the local microenvironment and the primary tumor. In fact, exosomes are secreted by both tumor and non-tumor cells, to provide a mutual communication network between cells and their micro- and/or macro-environments. Exososmes can contain a variety of biological cargos mostly based on their originated cells. Uptake of these exosomes by their recipient cells results in the alterations that their cargo can exert. MicroRNAs are identified as one of the most critical exosomal components, considering their pivotal regulatory roles in distinct biological process, including metastasis. Release and absorbance of exosomal microRNAs is possible by various cells within the host, and can have distinct biological consequences. Therefore, in this review we will discuss the role of exosomal microRNAs derived from tumor cells and untransformed cells within their micro- and macroenvironment in cancer progression and metastasis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Fahad Alsaikhan reports financial support was provided by Prince Sattam bin Abdulaziz University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

As a subset of mononuclear phagocytes in the central nervous system, microglia play a crucial role in immune defense and homeostasis maintenance. Microglia can regulate their states in response to specific signals of health and pathology. Microglia-mediated neuroinflammation is a pathological hallmark of neurodegenerative diseases, neurological damage and neurological tumors, underscoring its key immunoregulatory role in these conditions. Intriguingly, a substantial body of research has indicated that extracellular vesicles can mediate intercellular communication by transporting cargoes from parental cells, a property that is also reflected in microenvironmental signaling networks involving microglia. Based on the microglial characteristics, we briefly outline the biological features of extracellular vesicles and focus on summarizing the integrative role played by microglia in the maintenance of nervous system homeostasis and progression of different neurological diseases. Extracellular vesicles may engage in the homeostasis maintenance and pathological process as a medium of intercellular communication. Here, we aim to provide new insights for further exploration of neurological disease pathogenesis, which may provide theoretical foundations for cell-free therapies., Competing Interests: Declaration of competing interest The authors declare that they have no relevant financial or nonfinancial interests to disclose that are relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Extracellular vesicles (EVs) are vesicle-like bodies with a double membrane structure that are released from the cell membrane or secreted by cells into the extracellular environment. These include exosomes, microvesicles, and apoptotic bodies. There is growing evidence indicating that the composition of liver cell contents changes following injury. The quantity of EVs and the biologically active substances they carry vary depending on the condition of the liver cells. Hepatocytes utilize EVs to modulate the functions of different liver cells and transfer them to distant organs via the systemic circulation, thereby playing a crucial role in intercellular communication. This review provides a concise overview of the research on the effects and potential mechanisms of hepatocyte-derived EVs (Hep-EVs) on liver diseases and extrahepatic diseases under different physiological and pathological conditions. Common liver diseases discussed include non-alcoholic fatty liver disease (NAFLD), viral hepatitis, alcoholic liver disease, drug-induced liver damage, and liver cancer. Given that NAFLD is the most prevalent chronic liver disease globally, this review particularly highlights the use of hepatocyte-derived EVs in NAFLD for disease progression, diagnosis, and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cell junctions, including anchoring, occluding and communicating junctions, play an indispensable role in the structural and functional organization of multicellular tissues, including in liver. Specifically, hepatic cell junctions mediate intercellular adhesion and communication between liver cells. The establishment of the hepatic cell junction network is a prerequisite for normal liver functioning. Hepatic cell junctions indeed support liver-specific features and control essential aspects of the hepatic life cycle. This review paper summarizes the role of cell junctions and their components in relation to liver physiology, thereby also discussing their involvement in hepatic dysfunctionality, including liver disease and toxicity., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pathological vascular remodeling of the vessel wall refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease. The vessel wall is composed of two main types of cells, endothelial cells and vascular smooth muscle cells, whose communication is crucial in both the development of the vasculature and the homeostasis of mature vessels. Changes in the dialogue between endothelial cells and vascular smooth muscle cells are associated with various pathological states that triggers remodeling of the vascular wall. For many years, considerable efforts have been made to develop effective diagnoses and treatments for these pathologies by studying their mechanisms in both in vitro and in vivo models. Compared to animal models, in vitro models can provide great opportunities to obtain data in a more homogeneous, economical and massive way, providing an overview of the signaling pathways responsible for these pathologies. The implementation of three-dimensional in vitro co-culture models for the study of other pathologies has been postulated as a potentially applicable methodology, which determines the importance of its application in studies of cardiovascular diseases. In this article we present a method for culturing human endothelial cells and vascular smooth muscle cells, grown under non-adherent conditions, that generate three-dimensional spheroidal structures with greater physiological equivalence to in vivo conditions. This in vitro modeling could be used as a study tool to identify cellular and molecular mechanisms involved in the pathological processes underlying vascular remodeling., (Copyright © 2024 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

The integumentary system serves as a crucial protective barrier and is subject to complex signaling pathways that regulate its physiological functions. As the body's first line of defense, the skin is continuously exposed to environmental stressors, necessitating a robust network of signaling molecules to maintain homeostasis. Considering the main cellular components to be keratinocytes, melanocytes, fibroblasts, and fibrous components, collagen of various types, this review explores the intricate signaling mechanisms that govern skin integrity, focusing on key pathways involved in impacts of ageing and environment factors on skin health. The role of growth factors, cytokines, hormones and other molecular mediators in these processes is examined. Specially for women, decrease of estrogen is determinant to alter signaling and to compromise skin structure, especially the dermis. Environmental factors, such as ultraviolet rays and pollution alongside the impact of ageing on signaling pathways, especially TGF-β and proteases (metalloproteinases and cathepsins). Furthermore, with advancing age, the skin's capacity to shelter microbiome challenges diminishes, leading to alterations in signal transduction and subsequent functional decline. Understanding these age-related changes is essential for developing targeted therapies aimed at enhancing skin health and resilience, but also offers a promising avenue for the treatment of skin disorders and the promotion of healthy ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Recanalization therapy can significantly improve the prognosis of patients with acute myocardial infarction (AMI). However, infarction or reperfusion-induced cardiomyocyte death, immune cell infiltration, fibroblast proliferation, and scarring formation lead to cardiac remodeling and gradually progress to heart failure or arrhythmia, resulting in a high mortality rate. Due to the inability of cardiomyocytes to regenerate, the healing of infarcted myocardium mainly relies on the formation of scars. Cardiac fibroblasts, as the main effector cells involved in repair and scar formation, play a crucial role in maintaining the structural integrity of the heart after MI. Recent studies have revealed that exosome-mediated intercellular communication plays a huge role in myocardial repair and signaling transduction after myocardial infarction (MI). Exosomes can regulate the biological behavior of fibroblasts by activating or inhibiting the intracellular signaling pathways through their contents, which are derived from cardiomyocytes, immune cells, endothelial cells, mesenchymal cells, and others. Understanding the interactions between fibroblasts and other cell types during cardiac remodeling will be the key to breakthrough therapies. This review examines the role of exosomes from different sources in the repair process after MI injury, especially the impacts on fibroblasts during myocardial remodeling, and explores the use of exosomes in the treatment of myocardial remodeling after MI., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Feng et al.)

Small extracellular vesicles (sEV) are endogenous lipid-bound membrane vesicles secreted by both prokaryotic and eukaryotic cells into the extracellular environment, performs several biological functions such as cell-cell communication, transfer of proteins, mRNA, and ncRNA to target cells in distant sites. Due to their role in molecular pathogenesis and its potential to deliver biological cargo to target cells, it has become a prominent area of interest in recent research in the field of Neuroscience. However, their role in neurological disorders, like neurodegenerative diseases is more complex and still unaddressed. Thus, this review focuses on the role of sEV in neurodegenerative and neurodevelopmental diseases, including their biogenesis, classification, and pathogenesis, with translational advantages and limitations in the area of neurobiology., Competing Interests: Declaration of competing interest All authors declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The fate choices of stem cells between self-renewal and differentiation are often tightly regulated by juxtacrine (cell-cell contact) signalling. Here, we assess how the interplay between cell division, cell fate choices, and juxtacrine signalling can affect the macroscopic ordering of cell types in self-renewing epithelial sheets, by studying a simple spatial cell fate model with cells being arranged on a 2D lattice. We show in this model that if cells commit to their fate directly upon cell division, macroscopic patches of cells of the same type emerge, if at least a small proportion of divisions are symmetric, except if signalling interactions are laterally inhibiting. In contrast, if cells are first 'licensed' to differentiate, yet retaining the possibility to return to their naive state, macroscopic order only emerges if the signalling strength exceeds a critical threshold: if then the signalling interactions are laterally inducing, macroscopic patches emerge as well. Lateral inhibition, on the other hand, can in that case generate periodic patterns of alternating cell types (checkerboard pattern), yet only if the proportion of symmetric divisions is sufficiently low. These results can be understood theoretically by an analogy to phase transitions in spin systems known from statistical physics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Philip Greulich. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The traditional view of glial cells as mere supportive tissue has shifted, due to advances in technology and theoretical conceptualization, to include a diversity of other functions, such as regulation of complex behaviors. Astrocytes, the most abundant glial cells in the central nervous system (CNS), have been shown to modulate synaptic functions through gliotransmitter-mediated neurotransmitter reuptake, influencing neuronal signaling and behavioral functions. Contemporary studies further highlight astrocytes' involvement in complex cognitive functions. For instance, inhibiting astrocytes in the hippocampus can lead to memory deficits, suggesting their integral role in memory processes. Moreover, astrocytic calcium activity and astrocyte-neuron metabolic coupling have been linked to changes in synaptic strength and learning. Microglia, another type of glial cell, also extend beyond their supportive roles, contributing to learning and memory processes, with microglial reductions impacting these functions in a developmentally dependent manner. Oligodendrocytes, traditionally thought to have limited roles postdevelopment, are now recognized for their activity-dependent modulation of myelination and plasticity, thus influencing behavioral responses. Recent advancements in technology and computational modeling have expanded our understanding of glial functions, particularly how astrocytes influence neuronal circuits and behaviors. This review underscores the importance of glial cells in CNS functions and the need for further research to unravel the complexities of neuron-glia interactions, the impact of these interactions on brain functions, and potential implications for neurological diseases., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Communication between neurons and glia significantly influences the development maturation, plasticity, and disease progressions of the nervous system. As a new signaling modality, extracellular vesicles display a diverse role for robust functional regulation of neurons through their protein and nucleic acid cargoes. This review highlights recent breakthroughs in the research of signaling mechanisms between glia and neurons mediated by extracellular vesicles that are important for neural development, axonal maintenance, synaptic functions, and disease progression in the mammalian nervous system. We will discuss the biological roles of extracellular vesicles released from neurons, astroglia, microglia, and oligodendroglia in the nervous system and their implications in neurodegenerative disorders., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Red blood cells (RBCs) carry oxygen and make up 40-45% of blood by volume in large vessels down to 10% or less in smaller capillaries. Because of their finite size and large volume fraction, they are heterogeneously distributed throughout the body. This is partially because RBCs are distributed or partitioned nonuniformly at diverging vessel bifurcations where blood flows from one vessel into two. Despite its increased recognition as an important player in the microvasculature, few studies have explored how the endothelial surface layer (ESL; a vessel wall coating) may affect partitioning and RBC dynamics at diverging vessel bifurcations. Here, we use a mathematical and computational model to consider how altering ESL properties, as can occur in pathological scenarios, change RBC partitioning, deformation, and penetration of the ESL. The two-dimensional finite element model considers pairs of cells, represented by interconnected viscoelastic elements, passing through an ESL-lined diverging vessel bifurcation. The properties of the ESL include the hydraulic resistivity and an osmotic pressure difference modeling how easily fluid flows through the ESL and how easily the ESL is structurally compressed, respectively. We find that cell-cell interaction leads to more uniform partitioning and greatly enhances the effects of ESL properties, especially for deformation and penetration. This includes the trend that increased hydraulic resistivity leads to more uniform partitioning, increased deformation, and decreased penetration. It also includes the trend that decreased osmotic pressure increases penetration., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Tunneling nanotubes (TNTs) facilitate the exchange of intracellular cargo between cells. In this issue of Neuron, Scheiblich et al. 1 reveal that TNTs selectively mediate the bidirectional transfer of cytoplasmic protein aggregates from neurons to microglia and mitochondria from microglia to neurons, thereby preserving neuronal health., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological and pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, and proteins. In neurodegenerative diseases like Parkinson's and Alzheimer's disease, toxic aggregates of alpha-synuclein (α-syn) and tau accumulate within neurons. Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health. Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression. Disrupting mitochondrial function with antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing neurons with microglia and promoting TNT formation rescues suppressed neuronal activity caused by α-syn or tau aggregates. Notably, TNT-mediated aggregate transfer is compromised in microglia carrying Lrrk22(Gly2019Ser) or Trem2(T66M) and (R47H) mutations, suggesting a role in the pathology of these gene variants in neurodegenerative diseases., Competing Interests: Declaration of interests E.L. is a co-founder and advisor at IFM Therapeutics, and M.T.H. serves as an advisory board member at IFM Therapeutics, T3D, and Alector., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Formation of organs and specialized tissues in embryonic development requires migration of cells to specific targets. In some instances, such cells migrate as a robust cluster. We here explore a recent local approximation of non-local continuum models by Falcó et al. (SIAM J Appl Math 84:17-42, 2023). We apply their theoretical results by specifying biologically-based cell-cell interactions, showing how such cell communication results in an effective attraction-repulsion Morse potential. We then explore the clustering instability, the existence and size of the cluster, and its stability. For attractant-repellent chemotaxis, we derive an explicit condition on cell and chemical properties that guarantee the existence of robust clusters. We also extend their work by investigating the accuracy of the local approximation relative to the full non-local model., (© 2024. The Author(s), under exclusive licence to the Society for Mathematical Biology.)

Cell-cell communication (CCC) through ligand-receptor (L-R) pairs forms the cornerstone for complex functionalities in multicellular organisms. Deciphering such intercellular signaling can contribute to unraveling disease mechanisms and enable targeted therapy. Nonetheless, notable biases and inconsistencies are evident among the inferential outcomes generated by current methods for inferring CCC network. To fill this gap, we developed collectNET (http://health.tsinghua.edu.cn/collectnet) as a comprehensive web platform for analyzing CCC network, with efficient calculation, hierarchical browsing, comprehensive statistics, advanced searching, and intuitive visualization. collectNET provides a reliable online inference service with prior knowledge of three public L-R databases and systematic integration of three mainstream inference methods. Additionally, collectNET has assembled a human CCC atlas, including 126 785 significant communication pairs based on 343 023 cells. We anticipate that collectNET will benefit researchers in gaining a more holistic understanding of cell development and differentiation mechanisms. Database URL: http://health.tsinghua.edu.cn/collectnet., (© The Author(s) 2024. Published by Oxford University Press.)

Increasing evidences demonstrate the role of sensory innervation in bone metabolism, remodeling and repair, however neurovascular coupling in bone is rarely studied. Using microfluidic devices as an indirect co-culture model to mimic in vitro the physiological scenario of innervation, our group demonstrated that sensory neurons (SNs) were able to regulate the extracellular matrix remodeling by endothelial cells (ECs), in particular through sensory neuropeptides, i.e. calcitonin gene-related peptide (CGRP) and substance P (SP). Nonetheless, still little is known about the cell signaling pathways and mechanism of action in neurovascular coupling. Here, in order to characterize the communication between SNs and ECs at molecular level, we evaluated the effect of SNs and the neuropeptides CGRP and SP on ECs. We focused on different pathways known to play a role on endothelial functions: calcium signaling, p38 and Erk1/2; the control of signal propagation through Cx43; and endothelial functions through the production of nitric oxide (NO). The effect of SNs was evaluated on ECs Ca 2+ influx, the expression of Cx43, endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, p38, ERK1/2 as well as their phosphorylated forms. In addition, the role of CGRP and SP were either analyzed using respective antagonists in the co-culture model, or by adding directly on the ECs monocultures. We show that capsaicin-stimulated SNs induce increased Ca 2+ influx in ECs. SNs stimulate the increase of NO production in ECs, probably involving a decrease in the inhibitory eNOS T495 phosphorylation site. The neuropeptide CGRP, produced by SNs, seems to be one of the mediators of this effect in ECs since NO production is decreased in the presence of CGRP antagonist in the co-culture of ECs and SNs, and increased when ECs are stimulated with synthetic CGRP. Taken together, our results suggest that SNs play an important role in the control of the endothelial cell functions through CGRP production and NO signaling pathway., (© 2024. The Author(s).)

The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We have previously demonstrated a rapid secretion of matrix metalloproteinase-2 (MMP-2) in the ischemic brain. Since Scube2 can interact with Sonic hedgehog (Shh) to maintain blood-brain barrier (BBB) integrity via regulating the interaction between brain capillary endothelial cells (ECs) and perivascular astrocytes, and it is also a substrate of MMP-2, we hypothesized that the secreted MMP-2 could degrade Scube2 and contribute to ischemic BBB disruption. Using an in vitro ischemic model of 90-min oxygen-glucose deprivation/3-h reoxygenation (OGD/R) and an in vivo mouse stroke model of 90-min middle cerebral artery occlusion (MCAO) with 3-h reperfusion, we established an important role of MMP-2-mediated Scube2 degradation in early ischemic BBB disruption. Exposure of C8-D1A cells and bEnd.3 cells to OGD/R increased MMP secretion in both cells, and C8-D1A cells appeared to secrete more MMPs than bEnd.3 cells. Co-IP and double-immunostaining revealed that Scube2 co-localized well with MMP-2 in C8-D1A cells and could be pulled down by MMP-2 antibodies. In MCAO mice, Scube2 protein showed a drastic reduction in ischemic brain tissue, which was accompanied by suppressed expression of Shh and its downstream molecules. Of note, specific knockdown of astrocytic Scube2 with AAV-shScube2 augmented MCAO-induced Shh suppression and exacerbated BBB leakage and inflammatory reactions in the ischemic brain. Last, incubation of bEnd.3 cells with conditioned medium derived from OGD-treated C8-D1A cells led to a significant inhibition of the Shh pathway in bEnd.3 cells and degradation of VE-cadherin and ZO-1. Inhibition of MMP-2 with SB-3CT or over-expression of Scube2 with plasmids in C8-D1A cells alleviated the above effect of C8-D1A cells-derived conditioned medium. Taken together, our data indicate that ischemia-induced secretion of MMP-2 may contribute to early BBB disruption in ischemic stroke via interrupting the shared Scube2-Shh pathway between brain capillary ECs and perivascular astrocytes., (© 2023 International Society for Neurochemistry.)

Obesity is a metabolic disorder with pandemic-like implications, lacking viable pharmaceutical treatments currently. Thermogenic adipose tissues, including brown and beige adipose tissues, play an essential role in regulating systemic energy homeostasis and have emerged as appealing therapeutic targets for the treatment of obesity and obesity-related diseases. The function of adipocytes is subject to complex regulation by a cellular network of immune signaling pathways in response to environmental signals. However, the specific regulatory roles of immune cells in thermogenesis and relevant involving mechanisms are still not well understood. Here, we concentrate on our present knowledge of the interaction between thermogenic adipocytes and immune cells and present an overview of cellular and molecular mechanisms underlying immunometabolism in adipose tissues. We discuss cytokines, especially interleukins, which originate from widely variable sources, and their impacts on the development and function of thermogenic adipocytes. Moreover, we summarize the neuroimmune regulation in heat production and expand a new mode of intercellular communication mediated by mitochondrial transfer. The crosstalk between immune cells and adipocytes achieves adipose tissue homeostasis and systemic energy balance. A deep understanding of this intricate interaction would provide evidence for improving thermogenic efficiency by remodeling the immune microenvironment. Interventions based on these factors show a high potential to prevent adverse metabolic outcomes in patients with obesity.

Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid β, tau, ɑ-synuclein, prions, and TDP-43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood-brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Gap junctions are channels that allow for direct transmission of electrical signals between cells. However, the ability of one cell to be impacted or controlled by other cells through gap junctions remains unclear. In this study, heterocellular coupling between ON α retinal ganglion cells (α-RGCs) and displaced amacrine cells (ACs) in the mouse retina was used as a model. The impact of the extent of coupling of interconnected ACs on the synchronized firing between coupled ON α-RGC-AC pair was investigated using the dopamine 1 receptor (D1R) antagonist-SCH23390 and agonist-SKF38393. It was observed that the synchronized firing between the ON α-RGC-ACs pairs was increased by the D1R antagonist SCH23390, whereas it was eradicated by the agonist SKF38393. Subsequently, the signaling drive was investigated by infecting coupled ON α-RGC-AC pairs with the channelrhodopsin-2(ChR2) mutation L132C engineered to enhance light sensitivities. The results demonstrated that the spikes of ON α-RGCs (without ChR2) could be triggered by ACs (with ChR2) through the gap junction, and vice versa. Furthermore, it was observed that ON α-RGCs stimulated with 3-10 Hz currents by whole cell patch could elicit synchronous spikes in the coupled ACs, and vice versa. This provided direct evidence that the firing of one cell could be influenced by another cell through gap junctions. However, this phenomenon was not observed between OFF α-RGC pairs. The study implied that the synchronized firing between ON α-RGC-AC pairs could potentially be affected by the coupling of interconnected ACs. Additionally, one cell type could selectively control the firing of another cell type, thereby forcefully transmitting information. The key role of gap junctions in synchronizing firing and driving cells between α-RGCs and coupled ACs in the mouse retina was highlighted. NEW & NOTEWORTHY This study investigates the role of gap junctions in transmitting electrical signals between cells and their potential for cell control. Using ON α retinal ganglion cells (α-RGCs) and amacrine cells (ACs) in the mouse retina, the researchers find that the extent of coupling between ACs affects synchronized firing. Bidirectional signaling occurs between ACs and ON α-RGCs through gap junctions.

The development of innovative strategies for cell membranes engineering is of prime interest to explore and manipulate cell-cell interactions. Herein, an enzyme-sensitive recognition marker that can be introduced on cell surface via bioorthogonal chemistry is designed. Once functionalized in this fashion, the cells gain the ability to assemble with cell partners coated with the complementary marker through non-covalent click chemistry. The artificial cell adhesion induces natural biological processes associated with cell proximity such as inhibiting cancer cell proliferation and migration. On the other hand, the enzymatic activation of the stimuli-responsive marker triggers the disassembly of cells, thereby restoring the tumor cell proliferation and migration rates. Thus, the study shows that the ready-to-use complementary markers are valuable tools for controlling the formation and the breaking of bonds between cells, offering an easy way to investigate biological processes associated to cell proximity., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Modern bioelectronic tools are rapidly advancing to detect electric potentials within networks of electrogenic cells, such as cardiomyocytes, neurons, and pancreatic beta cells. However, it is becoming evident that electrical signaling is not limited to the animal kingdom but may be a universal form of cell-cell communication. In this review, we discuss the existing evidence of, and tools used to collect, subcellular, single-cell and network-level electrical signals across kingdoms, including bacteria, plants, fungi, and even viruses. We discuss how cellular networks employ altered electrical "circuitry" and intercellular mechanisms across kingdoms, and we assess the functionality and scalability of cutting-edge nanobioelectronics to collect electrical signatures regardless of cell size, shape, or function. Researchers today aim to design micro- and nano-topographic structures which harness mechanosensitive membrane and cytoskeletal pathways that enable tight electrical coupling to subcellular compartments within high-throughput recording systems. Finally, we identify gaps in current knowledge of inter-species and inter-kingdom electrical signaling and propose critical milestones needed to create a central theory of electrical signaling across kingdoms. Our discussion demonstrates the need for high resolution, high throughput tools which can probe multiple, diverse cell types at once in their native or experimentally-modeled environments. These advancements will not only reveal the underlying biophysical laws governing the universal language of electrical communication, but can enable bidirectional electrical communication and manipulation of biological systems., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Migrasomes are newly identified cellular organelles with a pomegranate-like structure and specifically generated by migrating cells. The mechanisms underlying migrasome biogenesis and methods for their isolation are gradually being elucidated. These organelles are pivotal in cell-to-cell communication and the maintenance of mitochondrial homeostasis. Their involvement in a diverse array of physiological and pathological processes is increasingly recognized. Despite these advancements, research on migrasomes is still in its early stages. It is imperative to delve deeper into the intricate mechanisms and functions of migrasomes to fully understand their role in physiopathology. In this review, we summarize the current research progress on migrasomes, including their distribution, biogenesis, purification and identification techniques, biological functionalities, and roles in physiological and pathological processes. We particularly highlight their potentials in disease diagnosis and therapy and point out the challenges facing us, aiming to provide novel insights into the emerging organelles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neurons are the primary cells responsible for information processing in the central nervous system (CNS). However, they are vulnerable to damage and insult in a variety of neurological disorders. As the most abundant glial cells in the brain, astrocytes provide crucial support to neurons and participate in synapse formation, synaptic transmission, neurotransmitter recycling, regulation of metabolic processes, and the maintenance of the blood-brain barrier integrity. Though astrocytes play a significant role in the manifestation of injury and disease, they do not work in isolation. Cellular interactions between astrocytes and neurons are essential for maintaining the homeostasis of the CNS under both physiological and pathological conditions. In this review, we explore the diverse interactions between astrocytes and neurons under physiological conditions, including the exchange of neurotrophic factors, gliotransmitters, and energy substrates, and different CNS diseases such as Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis. This review sheds light on the contribution of astrocyte-neuron crosstalk to the progression of neurological diseases to provide potential therapeutic targets for the treatment of neurological diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ectodermal organs, such as hair follicles, originate from simple epithelial and mesenchymal sheets through a complex developmental process driven by interactions between these cell types. This process involves dermal condensation, placode formation, bud morphogenesis, and organogenesis, and all of these processes require intricate interactions among various tissues. Recent research has emphasized the crucial role of reciprocal and dynamic interactions between cells and the extracellular matrix (ECM), referred to as the "dynamic duo", in the development of ectodermal organs. These interactions provide spatially and temporally changing biophysical and biochemical cues within tissues. Using the hair follicle as an example, this review highlights two types of cell-ECM adhesion units-focal adhesion-type and hemidesmosome-type adhesion units-that facilitate communication between epithelial and mesenchymal cells. This review further explores how these adhesion units, along with other cell-ECM interactions, evolve during hair follicle development and regeneration, underscoring their importance in guiding both developmental and regenerative processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Optically actuated soft microrobotic tools were designed for cell transportation, manipulation, and cell-to-cell interactions.

Hypoxia, as a prominent feature of the tumor microenvironment, has a profound impact on the multicomponent changes within this environment. Under hypoxic conditions, the malignant phenotype of tumor cells, the variety of cell types within the tumor microenvironment, as well as intercellular communication and material exchange, undergo complex alterations. These changes provide significant prospects for exploring the mechanisms of tumor development under different microenvironmental conditions and for devising therapeutic strategies. Exosomes secreted by tumor cells and stromal cells are integral components of the tumor microenvironment, serving as crucial mediators of intercellular communication and material exchange, and have consequently garnered increasing attention from researchers. This review focuses on the mechanisms by which hypoxic conditions promote the release of exosomes by tumor cells and alter their encapsulated contents. It also examines the effects of exosomes derived from tumor cells, immune cells, and other cell types under hypoxic conditions on the tumor microenvironment. Additionally, we summarize current research progress on the potential clinical applications of exosomes under hypoxic conditions and propose future research directions in this field., Competing Interests: These authors declare that they have no conflicts of interest in this work., (© 2024 Wang et al.)

Valve remodeling is a process involving extracellular matrix organization and elongation of valve leaflets. Here, through single-cell RNA sequencing of human fetal valves, we identified an elastin-producing valve interstitial cell (VIC) subtype (apolipoprotein E (APOE) + , elastin-VICs) spatially located underneath valve endothelial cells (VECs) sensing unidirectional flow. APOE knockdown in fetal VICs resulted in profound elastogenesis defects. In valves with pulmonary stenosis (PS), we observed elastin fragmentation and decreased expression of APOE along with other genes regulating elastogenesis. Cell-cell interaction analysis revealed that jagged 1 (JAG1) from unidirectional VECs activates elastogenesis in elastin-VICs through NOTCH2. Similar observations were made in VICs cocultured with VECs under unidirectional flow. Notably, a drastic reduction of JAG1-NOTCH2 was also observed in PS valves. Lastly, we found that APOE controls JAG1-induced NOTCH activation and elastogenesis in VICs through the extracellular signal-regulated kinase pathway. Our study suggests important roles of both APOE and NOTCH in regulating elastogenesis during human valve remodeling., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The liver possesses a distinctive capacity for regeneration within the human body. Under normal circumstances, liver cells replicate themselves to maintain liver function. Compensatory replication of healthy hepatocytes is sufficient for the regeneration after acute liver injuries. In the late stage of chronic liver damage, a large number of hepatocytes die and hepatocyte replication is blocked. Liver regeneration has more complex mechanisms, such as the transdifferentiation between cell types or hepatic progenitor cells mediated. Dysregulation of liver regeneration causes severe chronic liver disease. Gaining a more comprehensive understanding of liver regeneration mechanisms would facilitate the advancement of efficient therapeutic approaches. This review provides an overview of the signalling pathways linked to different aspects of liver regeneration in various liver diseases. Moreover, new knowledge on cellular interactions during the regenerative process is also presented. Finally, this paper explores the potential applications of new technologies, such as nanotechnology, stem cell transplantation and organoids, in liver regeneration after injury, offering fresh perspectives on treating liver disease., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Exosomes are a subgroup of extracellular vesicles that function as transmitters, allowing cells to communicate more effectively with each other. However, exosomes may have both beneficial and harmful impacts on central nervous system disorders. Hence, the fundamental molecular mechanisms of the origin of illness and its progression are currently being investigated. The involvement of exosomes in the origin and propagation of neurodegenerative illness has been demonstrated recently. Exosomes provide a representation of the intracellular environment since they include various essential bioactive chemicals. The latest studies have demonstrated that exosomes transport several proteins. Additionally, these physiological vesicles are important in the regeneration of nervous tissue and the healing of neuronal lesions. They also offer a microenvironment to stimulate the conformational variation of concerning proteins for aggregation, resulting in neurodegenerative diseases. The biosynthesis, composition, and significance of exosomes as extracellular biomarkers in neurodegenerative disorders are discussed in this article, with a particular emphasis on their neuroprotective effects., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest, (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Proteins on the surfaces of cells serve as physical connection points to bridge one cell with another, enabling direct communication between cells and cohesive structure. As biomedical research makes the leap from characterizing individual cells toward understanding the multicellular organization of the human body, the binding interactions between molecules on the surfaces of cells are foundational both for computational models and for clinical efforts to exploit these influential receptor pathways. To achieve this grander vision, we must assemble the full interactome of ways surface proteins can link together. This review investigates how close we are to knowing the human cell surface protein interactome. We summarize the current state of databases and systematic technologies to assemble surface protein interactomes, while highlighting substantial gaps that remain. We aim for this to serve as a road map for eventually building a more robust picture of the human cell surface protein interactome.

Background and Purpose: The single layer of cells lining all blood vessels, the endothelium, is a sophisticated signal co-ordination centre that controls a wide range of vascular functions including the regulation of blood pressure and blood flow. To co-ordinate activities, communication among cells is required for tissue level responses to emerge. While a significant form of communication occurs by the propagation of signals between cells, the mechanism of propagation in the intact endothelium is unresolved., Experimental Approach: Precision signal generation and targeted cellular manipulation was used in conjunction with high spatiotemporal mesoscale Ca 2+ imaging in the endothelium of intact blood vessels., Key Results: Multiple mechanisms maintain communication so that Ca 2+ wave propagation occurs irrespective of the status of connectivity among cells. Between adjoining cells, regenerative IP 3 -induced IP 3 production transmits Ca 2+ signals and explains the propagated vasodilation that underlies the increased blood flow accompanying tissue activity. The inositide is itself sufficient to evoke regenerative phospholipase C-dependent Ca 2+ waves across coupled cells. None of gap junctions, Ca 2+ diffusion or the release of extracellular messengers is required to support this type of intercellular Ca 2+ signalling. In contrast, when discontinuities exist between cells, ATP released as a diffusible extracellular messenger transmits Ca 2+ signals across the discontinuity and drives propagated vasodilation., Conclusion and Implications: These results show that signalling switches underlie endothelial cell-to-cell signal transmission and reveal how communication is maintained in the face of endothelial damage. The findings provide a new framework for understanding wave propagation and cell signalling in the endothelium., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Extracellular elastin-derived peptides (EDPs) accumulate in the aging brain and have been associated with vascular dementia and Alzheimer's disease (AD). The activation of inflammatory processes in glial cells with EDP treatment has received attention, but not in neurons. To properly understand EDPs' pathogenic significance, the impact on neuronal function and neuron-microglia crosstalk was explored further. Among the EDP molecules, Val-Gly-Val-Ala-Pro-Gly (VGVAPG) is a typical repeating hexapeptide. Here, we observed that EDPs-VGVAPG influenced neuronal survival and morphology in a dose-dependent manner. High concentrations of VGVAPG induced synapse loss and microglia hyperactivation in vivo and in vitro. Following EDP incubation, galectin 3 (Gal-3) released by neurons served as a chemokine, attracting microglial engulfment. Blocking Gal-3 and EDP binding remedied synapse loss in neurons and phagocytosis in microglia. In response to the accumulation of EDPs, proteomics in matrix remodeling and cytoskeleton dynamics, such as a disintegrin and metalloproteinase (ADAM) family, were engaged. These findings in extracellular EDPs provided more evidence for the relationship between aging and neuron dysfunction, increasing the insight of neuroinflammatory responses and the development of new specialized extracellular matrix remolding-targeted therapy options for dementia or other neurodegenerative disease., (© 2024 International Society for Neurochemistry.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Leech et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The shoot meristem of land plants maintains the capacity for organ generation throughout its lifespan due to a group of undifferentiated stem cells. Most meristems are shaped like a dome with a precise spatial arrangement of functional domains, and, within and between these domains, cells interact through a network of interconnected signaling pathways. Intercellular communication in meristems is mediated by mobile transcription factors, small RNAs, hormones, and secreted peptides that are perceived by membrane-localized receptors. In recent years, we have gained deeper insight into the underlying molecular processes of the shoot meristem, and we discuss here how plants integrate internal and external inputs to control shoot meristem activities.

Extracellular vesicles (EVs) serve as a crucial method for transferring information among cells, which is vital in multicellular organisms. Among these vesicles, exosomes are notable for their small size, ranging from 20 to 150 nm, and their role in cell-to-cell communication. They carry lipids, proteins, and nucleic acids between cells. The creation of exosomes begins with the inward budding of the cell membrane, which then encapsulates various macromolecules as cargo. Once filled, exosomes are released into the extracellular space and taken up by target cells via endocytosis and similar processes. The composition of exosomal cargo varies, encompassing diverse macromolecules with specific functions. Because of their significant roles, exosomes have been isolated from various cell types, including cancer cells, endothelial cells, macrophages, and mesenchymal cells, with the aim of harnessing them for therapeutic applications. Exosomes influence cellular metabolism, and regulate lipid, glucose, and glutamine pathways. Their role in pathogenesis is determined by their cargo, which can manipulate processes such as apoptosis, proliferation, inflammation, migration, and other molecular pathways in recipient cells. Non-coding RNA transcripts, a common type of cargo, play a pivotal role in regulating disease progression. Exosomes are implicated in numerous biological and pathological processes, including inflammation, cancer, cardiovascular diseases, diabetes, wound healing, and ischemic-reperfusion injury. As a result, they hold significant potential in the treatment of both cancerous and non-cancerous conditions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin-angiotensin-aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons., Result: The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes., Conclusion: Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context., (© 2024. The Author(s).)

Chirality plays a crucial role in biology, as it is highly conserved and fundamentally important in the developmental process. To better understand the relationship between the chirality of individual cells and that of tissues and organisms, we develop a generalized mechanics model of chiral polarized particles to investigate the swirling dynamics of cell populations on substrates. Our analysis reveals that cells with the same chirality can form distinct chiral patterns on ring-shaped or rectangular substrates. Interestingly, our studies indicate that an excessively strong or weak individual cellular chirality hinders the formation of such chiral patterns. Our studies also indicate that there exists the influence distance of substrate boundaries in chiral patterns. Smaller influence distances are observed when cell-cell interactions are weaker. Conversely, when cell-cell interactions are too strong, multiple cells tend to be stacked together, preventing the formation of chiral patterns on substrates in our analysis. Additionally, we demonstrate that the interaction between cells and substrate boundaries effectively controls the chiral distribution of cellular orientations on ring-shaped substrates. This research highlights the significance of coordinating boundary features, individual cellular chirality, and cell-cell interactions in governing the chiral movement of cell populations and provides valuable mechanics insights into comprehending the intricate connection between the chirality of single cells and that of tissues and organisms., Competing Interests: Competing interests statement:The authors declare no competing interest.

Exploring cell-cell communication is pivotal for understanding biological processes in multicellular life forms. Here, we present a protocol that details the use of matrix decomposition to infer cell-cell communication (MDIC3) for unsupervised cell-cell communication inference. We describe steps for using the MDIC3 Python scripts to deduce cell-cell communication and identify key ligand-receptor pairs between a specific cell type pair from a single-cell gene expression dataset. This protocol has potential application in cell-cell communication inference on any species. For complete details on the use and execution of this protocol, please refer to Liu et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cancer therapy often leads to the selective elimination of drug-sensitive cells from the tumour. This can favour the growth of cells resistant to the therapeutic agent, ultimately causing a tumour relapse. Castration-resistant prostate cancer (CRPC) is a well-characterised instance of this phenomenon. In CRPC, after systemic androgen deprivation therapy (ADT), a subset of drug-resistant cancer cells autonomously produce testosterone, thus enabling tumour regrowth. A previous theoretical study has shown that such a tumour relapse can be delayed by inhibiting the growth of drug-resistant cells using biotic competition from drug-sensitive cells. In this context, the centrality of resource dynamics to intra-tumour competition in the CRPC system indicates clear scope for the construction of theoretical models that can explicitly incorporate the underlying mechanisms of tumour ecology. In the current study, we use a modified logistic framework to model cell-cell interactions in terms of the production and consumption of resources. Our results show that steady state composition of CRPC can be understood as a composite function of the availability and utilisation efficiency of two resources-oxygen and testosterone. In particular, we show that the effect of changing resource availability or use efficiency is conditioned by their general abundance regimes. Testosterone typically functions in trace amounts and thus affects steady state behaviour of the CRPC system differently from oxygen, which is usually available at higher levels. Our data thus indicate that explicit consideration of resource dynamics can produce novel and useful mechanistic understanding of CRPC. Furthermore, such a modelling approach also incorporates variables into the system's description that can be directly measured in a clinical context. This is therefore a promising avenue of research in cancer ecology that could lead to therapeutic approaches that are more clearly rooted in the biology of CRPC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rationale: Extracellular vesicles (EVs) are thought to mediate intercellular communication during development and disease. Yet, biological insight to intercellular EV transfer remains elusive, also in the heart, and is technically challenging to demonstrate. Here, we aimed to investigate biological transfer of cardiomyocyte-derived EVs in the neonatal heart. Methods: We exploited CD9 as a marker of EVs, and generated two lines of cardiomyocyte specific EV reporter mice: Tnnt2-Cre ; double-floxed inverted CD9/EGFP and αMHC-MerCreMer; double-floxed inverted CD9/EGFP . The two mouse lines were utilized to determine whether developing cardiomyocytes transfer EVs to other cardiac cells (non-myocytes and cardiomyocytes) in vitro and in vivo and investigate the intercellular transport pathway of cardiomyocyte-derived EVs. Results: Genetic tagging of cardiomyocytes was confirmed in both reporter mouse lines and proof of concept in the postnatal heart showed that, a fraction of EGFP + /MYH1 - non-myocytes exist firmly demonstrating in vivo cardiomyocyte-derived EV transfer. However, two sets of direct and indirect EGFP +/- cardiac cell co-cultures showed that cardiomyocyte-derived EGFP + EV transfer requires cell-cell contact and that uptake of EGFP + EVs from the medium is limited. The same was observed when co-cultiring with mouse macrophages. Further mechanistic insight showed that cardiomyocyte EV transfer occurs through type I tunneling nanotubes. Conclusion: While the current notion assumes that EVs are transferred through secretion to the surroundings, our data show that cardiomyocyte-derived EV transfer in the developing heart occurs through nanotubes between neighboring cells. Whether these data are fundamental and relate to adult hearts and other organs remains to be determined, but they imply that the normal developmental process of EV transfer goes through cell-cell contact rather than through the extracellular compartment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

We discuss the mathematical modelling of two of the main mechanisms that pushed forward the emergence of multicellularity: phenotype divergence in cell differentiation and between-cell cooperation. In line with the atavistic theory of cancer, this disease being specific of multicellular animals, we set special emphasis on how both mechanisms appear to be reversed, however not totally impaired, rather hijacked, in tumour cell populations. Two settings are considered: the completely innovating, tinkering, situation of the emergence of multicellularity in the evolution of species, which we assume to be constrained by external pressure on the cell populations, and the completely planned-in the body plan-situation of the physiological construction of a developing multicellular animal from the zygote, or of bet hedging in tumours, assumed to be of clonal formation, although the body plan is largely-but not completely-lost in its constituting cells. We show how cancer impacts these two settings and we sketch mathematical models for them. We present here our contribution to the question at stake with a background from biology, from mathematics and from philosophy of science., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)