Communicating Across Cell Walls: Structure, Evolution, and Regulation of Plasmodesmatal Transport in Plants.

Plasmodesmata are conduits in plant cell walls that allow neighboring cells to communicate and exchange resources. Despite their central importance to plant development and physiology, our understanding of plasmodesmata is relatively limited compared to other subcellular structures. In recent years, technical advances in electron microscopy, mass spectrometry, and phylogenomics have illuminated the structure, composition, and evolution of plasmodesmata in diverse plant lineages. In parallel, forward genetic screens have revealed key signaling pathways that converge to regulate plasmodesmatal transport, including chloroplast-derived retrograde signaling, phytohormone signaling, and metabolic regulation by the conserved eukaryotic Target of Rapamycin kinase. This review summarizes our current knowledge of the structure, evolution, and regulation of plasmodesmatal transport in plants.

Airineme-Mediated Intercellular Communication.

Intercellular communication is indispensable across multicellular organisms, and any aberration in this process can give rise to significant anomalies in developmental and homeostatic processes. Thus, a comprehensive understanding of its mechanisms is imperative for addressing human health-related concerns. Recent advances have expanded our understanding of intercellular communication by elucidating additional signaling modalities alongside established mechanisms. Notably, cellular protrusion-mediated long-range communication, characterized by physical contact through thin and elongated cellular protrusions between cells involved in signal transmission and reception, has emerged as a significant intercellular signaling paradigm. This chapter delves into the exploration of a signaling cellular protrusion termed 'airinemes,' discovered in the zebrafish skin. It covers their identified signaling roles and the cellular and molecular mechanisms that underpin their functionality.

Intercellular Communication Through Microtubular Highways.

Tunneling nanotubes (TNTs) are open-ended, membrane-encased extensions that connect neighboring cells. They have diameters up to 1 µm but are able to expand to convey large cargos. Lengths vary depending on the distance of the cells but have been reported to be capable of extending beyond 300 µm. They have actin cytoskeletons that are essential for their formation, and may or may not have microtubule networks. It is thought that thin TNTs lack microtubules, while thicker TNTs have microtubular highways that use motor proteins to convey materials, including proteins, mitochondria, and nanoparticles between cells. Specifically, the presence of dynein and myosin support trafficking of cargo in both directions. The purpose of these connections is to enable cells to work as a unit or to extend cell life by diluting cytotoxic agents or acquiring biological material needed to survive.

Intercellular Highways in Transport Processes.

Communication among cells is vital in multicellular organisms. Various structures and mechanisms have evolved over time to achieve the intricate flow of material and information during this process. One such way of communication is through tunnelling membrane nanotubes (TNTs), which were initially described in 2004. These TNTs are membrane-bounded actin-rich cellular extensions, facilitating direct communication between distant cells. They exhibit remarkable diversity in terms of structure, morphology, and function, in which cytoskeletal proteins play an essential role. Biologically, TNTs play a crucial role in transporting membrane components, cell organelles, and nucleic acids, and they also present opportunities for the efficient transmission of bacteria and viruses, furthermore, may contribute to the dissemination of misfolded proteins in certain neurodegenerative diseases. Convincing results of studies conducted both in vitro and in vivo indicate that TNTs play roles in various biomedical processes, including cell differentiation, tissue regeneration, neurodegenerative diseases, immune response and function, as well as tumorigenesis.

Tunneling Nanotubes in the Brain.

Tunneling nanotubes (TNTs) have emerged as intriguing structures facilitating intercellular communications across diverse cell types, which are integral to several biological processes, as well as participating in various disease progression. This review provides an in-depth analysis of TNTs, elucidating their structural characteristics and functional roles, with a particular focus on their significance within the brain environment and their implications in neurological and neurodegenerative disorders. We explore the interplay between TNTs and neurological diseases, offering potential mechanistic insights into disease progression, while also highlighting their potential as viable therapeutic targets. Additionally, we address the significant challenges associated with studying TNTs, from technical limitations to their investigation in complex biological systems. By addressing some of these challenges, this review aims to pave the way for further exploration into TNTs, establishing them as a central focus in advancing our understanding of neurodegenerative disorders.

Orchestrating Blood Flow in the Retina: Interpericyte Tunnelling Nanotube Communication.

The retina transforms light into electrical signals, which are sent to the brain via the optic nerve to form our visual perception. This complex signal processing is performed by the retinal neuron and requires a significant amount of energy. Since neurons are unable to store energy, they must obtain glucose and oxygen from the bloodstream to produce energy to match metabolic needs. This process is called neurovascular coupling (NVC), and it is based on a precise mechanism that is not totally understood. The discovery of fine tubular processes termed tunnelling nanotubes (TNTs) set a new type of cell-to-cell communication. TNTs are extensions of the cellular membrane that allow the transfer of material between connected cells. Recently, they have been reported in the brain and retina of living mice, where they connect pericytes, which are vascular mural cells that regulate vessel diameter. Accordingly, these TNTs were termed interpericyte tunnelling nanotubes (IPTNTs), which showed a vital role in blood delivery and NVC. In this chapter, we review the involvement of TNTs in NVC and discuss their implications in retinal neurodegeneration.

Exosome Mediated Cell-Cell Crosstalk in Tissue Injury and Repair.

The landscape of exosome research has undergone a significant paradigm shift, with a departure from early conceptions of exosomes as vehicles for cellular waste disposal towards their recognition as integral components of cellular communication with therapeutic potential. This chapter presents an exhaustive elucidation of exosome biology, detailing the processes of exosome biogenesis, release, and uptake, and their pivotal roles in signal transduction, tissue repair, regeneration, and intercellular communication. Additionally, the chapter highlights recent innovations and anticipates future directions in exosome research, emphasizing their applicability in clinical settings. Exosomes have the unique ability to navigate through tissue spaces to enter the circulatory system, positioning them as key players in tissue repair. Their contributory role in various processes of tissue repair, although in the nascent stages of investigation, stands out as a promising area of research. These vesicles function as a complex signaling network for intracellular and organ-level communication, critical in both pathological and physiological contexts. The chapter further explores the tissue-specific functionality of exosomes and underscores the advancements in methodologies for their isolation and purification, which have been instrumental in expanding the scope of exosome research. The differential cargo profiles of exosomes, dependent on their cellular origin, position them as prospective diagnostic biomarkers for tissue damage and regenerative processes. Looking ahead, the trajectory of exosome research is anticipated to bring transformative changes to biomedical fields. This includes advancing diagnostic and prognostic techniques that utilize exosomes as non-invasive biomarkers for a plethora of diseases, such as cancer, neurodegenerative, and cardiovascular conditions. Additionally, engineering exosomes through alterations of their native content or surface properties presents a novel frontier, including the synthesis of artificial or hybrid variants with enhanced functional properties. Concurrently, the ethical and regulatory frameworks surrounding exosome research, particularly in clinical translation, will require thorough deliberation. In conclusion, the diverse aspects of exosome research are coalescing to redefine the frontiers of diagnostic and therapeutic methodologies, cementing its importance as a discipline of considerable consequence in the biomedical sciences.

Mechanisms of Intracellular Communication in Cancer and Pathogen Spreading.

Cell-to-cell interactions are essential for proper development, homeostasis, and complex syncytia/organ formation and function. Intercellular communication are mediated by multiple mechanisms including soluble mediators, adhesion molecules and specific mechanisms of cell to cell communication such as Gap junctions (GJ), tunneling nanotubes (TNT), and exosomes. Only recently, has been discovered that TNTs and exosomes enable the exchange of large signaling molecules, RNA, viral products, antigens, and organelles opening new avenues of research and therapeutic approaches. The focus of this review is to summarize these recent findings in physiologic and pathologic conditions.

Intercellular Molecular Transfer Mediated by Extracellular Vesicles in Cancer.

Among multiple pathways of intercellular communication operative in multicellular organisms, the trafficking of extracellular vesicles (EVs) and particles (EP) represents a unique mode of cellular information exchange with emerging roles in health and disease, including cancer. A distinctive feature of EV/EP-mediated cell-cell communication is that it involves simultaneous short- or long-range transfer of numerous molecular constituents (cargo) from donor to recipient cells. EV/EP uptake by donor cells elicits signalling or metabolic responses, or else leads to EV-re-emission or degradation. EVs are heterogeneous membranous structures released from cells via increasingly defined mechanisms involving either formation of multivesicular endosomes (exosomes) or budding from the plasma membrane (ectosomes). EPs (exomeres, supermeres) are membraneless complex particles, smaller than EVs and of less defined biogenesis and function. EVs/EPs carry complex assemblies of proteins, lipids and nucleic acids (RNA, DNA), which they shuttle into intercellular milieu, body fluids and recipient cells, via surface contact, fusion and different forms of internalization (endocytosis, micropinocytosis). While the physiological functions of EVs/EPs communication pathways continue to be investigated, their roles in cancer are increasingly well-defined. For example, EVs are involved in the transmission of cancer-specific molecular cargo, including mutant, oncogenic, transforming, or regulatory macromolecules to indolent, or normal cells, sometimes triggering their quasi-transformation-like states, or phenotypic alterations. Conversely, a reciprocal and avid uptake of stromal EVs by cancer cells may be responsible for modulating their oncogenic repertoire, as exemplified by the angiocrine effects of endothelial EVs influencing cancer cell stemness. EV exchanges during cancer progression have also been implicated in the formation of tumour stroma, angiogenesis and non-angiogenic neovascularization processes, immunosuppression, colonization of metastatic organ sites (premetastatic niche), paraneoplastic and systemic pathologies (thrombosis, diabetes, hepatotoxicity). Thus, an EV/EP-mediated horizontal transfer of cellular content emerges as a new dimension in cancer pathogenesis with functional, diagnostic, and therapeutic implications.

Tunneling Nanotubes in Myeloid Cells: Perspectives for Health and Infectious Diseases.

Tunneling nanotubes (TNTs) are cellular connections, which represent a novel route for cell-to-cell communication. Strong evidence points to a role for TNTs in the intercellular transfer of signals, molecules, organelles, and pathogens, involving them in many cellular functions. In myeloid cells (e.g., monocytes/macrophages, dendritic cells, and osteoclasts), intercellular communication via TNT contributes to their differentiation and immune functions, by favoring material and pathogen transfer, as well as cell fusion. This chapter addresses the complexity of the definition and characterization of TNTs in myeloid cells, the different processes involved in their formation, their existence in vivo, and finally their function(s) in health and infectious diseases, with the example of HIV-1 infection.

Hypoxia-Driven Changes in Tumor Microenvironment: Insights into Exosome-Mediated 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.

Emerging role and translational potential of small extracellular vesicles in neuroscience.

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.

Astrocyte-Neuron Interactions in Substance Use Disorders.

Engagement of astrocytes within the brain's reward circuitry has been apparent for approximately 30 years, when noncontingent drug administration was observed to lead to cytological markers of reactive astrocytes. Since that time, advanced approaches in rodent behavior and astrocyte monitoring have revealed complex interactions between astrocytes with drug type, animal sex, brain region, and dose and duration of drug administration. A number of studies now collectively reveal that rodent drug self-administration followed by prolonged abstinence results in decreased features of structure and synaptic colocalization of astrocytes. In addition, stimulation of astrocytes in the nucleus accumbens with DREADD receptors or pharmacological compounds opposes drug-seeking behavior. These findings provide a clear path for ongoing investigation into astrocytes as mediators of drug action in the brain and underscore the potential therapeutic utility of astrocytes in the regulation of drug craving and relapse vulnerability.

Astrocyte-Neuron Interactions in Spinal Cord Injury.

Spinal cord injuries cause irreversible loss of sensory and motor functions. In mammals, intrinsic and extrinsic inhibitions of neuronal regeneration obstruct neural repair after spinal cord injury. Although astrocytes have been involved in a growing list of vital homeostatic functions in the nervous system, their roles after injury have fascinated and puzzled scientists for decades. Astrocytes undergo long-lasting morphological and functional changes after injury, referred to as reactive astrogliosis. Although reactive astrogliosis is required to contain spinal cord lesions and restore the blood-spinal cord barrier, reactive astrocytes have detrimental effects that inhibit neuronal repair and remyelination. Intriguingly, elevated regenerative capacity is preserved in some non-mammalian vertebrates, where astrocyte-like glial cells display exclusively pro-regenerative effects after injury. A detailed molecular and phenotypic catalog of the continuum of astrocyte reactivity states is an essential first step toward the development of glial cell manipulations for spinal cord repair.

Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.

Amyotrophic lateral sclerosis (ALS) is a complex disease impacting motor neurons of the brain, brainstem, and spinal cord. Disease etiology is quite heterogeneous with over 40 genes causing the disease and a vast ~90% of patients having no prior family history. Astrocytes are major contributors to ALS, particularly through involvement in accelerating disease progression. Through study of genetic forms of disease including SOD1, TDP43, FUS, C9orf72, VCP, TBK1, and more recently patient-derived cells from sporadic individuals, many biological mechanisms have been identified to cause intrinsic or glial-mediated neurotoxicity to motor neurons. Overall, many of the normally supportive and beneficial roles that astrocytes contribute to neuronal health and survival instead switch to become deleterious and neurotoxic. While the exact pathways may differ based on disease-origin, altered astrocyte-neuron communication is a common feature of ALS. Within this chapter, distinct genetic forms are examined in detail, along with what is known from sporadic patient-derived cells. Overall, this chapter highlights the interplay between astrocytes and neurons in this complex disease and describes the key features underlying: astrocyte-mediated motor neuron toxicity, excitotoxicity, oxidative/nitrosative stress, protein dyshomeostasis, metabolic imbalance, inflammation, trophic factor withdrawal, blood-brain/blood-spinal cord barrier involvement, disease spreading, and the extracellular matrix/cell adhesion/TGF-ß signaling pathways.

Astrocyte-Neuron Interactions in Alzheimer's Disease.

Besides its two defining misfolded proteinopathies-Aß plaques and tau neurofibrillary tangles-Alzheimer's disease (AD) is an exemplar of a neurodegenerative disease with prominent reactive astrogliosis, defined as the set of morphological, molecular, and functional changes that astrocytes suffer as the result of a toxic exposure. Reactive astrocytes can be observed in the vicinity of plaques and tangles, and the relationship between astrocytes and these AD neuropathological lesions is bidirectional so that each AD neuropathological hallmark causes specific changes in astrocytes, and astrocytes modulate the severity of each neuropathological feature in a specific manner. Here, we will review both how astrocytes change as a result of their chronic exposure to AD neuropathology and how those astrocytic changes impact each AD neuropathological feature. We will emphasize the repercussions that AD-associated reactive astrogliosis has for the astrocyte-neuron interaction and highlight areas of uncertainty and priorities for future research.

Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations.

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.

Contactomics of Microglia and Intercellular Communication.

Microglia represent the main immunocompetent cell type in the parenchyma of the brain and the spinal cord, with roles extending way beyond their immune functions. While emerging data show the pivotal role of microglia in brain development, brain health and brain diseases, the exact mechanisms through which microglia contribute to complex neuroimmune interactions are still largely unclear. Understanding the communication between microglia and other cells represents an important cornerstone of these interactions, which may provide novel opportunities for therapeutic interventions in neurological or psychiatric disorders. As such, in line with studying the effects of the numerous soluble mediators that influence neuroimmune processes, attention on physical interactions between microglia and other cells in the CNS has increased substantially in recent years. In this chapter, we briefly summarize the latest literature on "microglial contactomics" and its functional implications in health and disease.