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Diabetic nephropathy, a common and severe complication of diabetes, is the leading cause of end-stage renal disease, ultimately leading to renal failure and significantly affecting the prognosis and lives of diabetics worldwide. However, the complexity of its developmental mechanisms makes treating diabetic nephropathy a challenging task, necessitating the search for improved therapeutic targets. Intercellular communication underlies the direct and indirect influence and interaction among various cells within a tissue. Recently, studies have shown that beyond traditional communication methods, tunnel nanotubes, exosomes, filopodial tip vesicles, and the fibrogenic niche can influence pathophysiological changes in diabetic nephropathy by disrupting intercellular communication. Therefore, this paper aims to review the varied roles of intercellular communication in diabetic nephropathy, focusing on recent advances in this area. [ABSTRACT FROM AUTHOR]

Background: Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation. Methods: MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography. Result: Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p < 0.05). Western blotting revealed the significant reduction of Rab8 and p-FAK in 3-MA-treated MSCs (p < 0.05), indicating the inhibition of TNT assembly and vesicle transport. Likewise, the stimulation of autophagy increased autophagic flux and mitochondrial membrane integrity compared to 3-MA-treated MSCs. Despite these findings, protein levels of mitochondrial membrane Miro1 and 2 were unchanged after autophagy inhibition/stimulation (p > 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator. Conclusions: In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma represents the majority of all liver cancers and the fourth cause of cancer-related deaths worldwide. Despite the progress in diagnostic and therapeutic evaluation, its prognosis remains dismal, with mortality rates increasing per year. As the investigation of the human genome project advances, so does the deeper understanding of tumor biology, with numerous molecular biomarkers proved to play a promising role in clinical practice, in terms of diagnosis, surveillance, and the prediction of treatment efficacy. One important aspect is evaluating the potential role of new ancillary biomarkers associated with tumor invasiveness and response to available therapeutic options, which is useful in treatment monitoring and may reduce the health costs faced by standard methods. Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential. [ABSTRACT FROM AUTHOR]

Cancer progression is continuously controlled by the immune system which can identify and destroy nascent tumor cells or inhibit metastatic spreading. However, the immune system and its deregulated activity in the tumor microenvironment can also promote tumor progression favoring the outgrowth of cancers capable of escaping immune control, in a process termed cancer immunoediting. This process, which has been classified into three phases, i.e. "elimination", "equilibrium" and "escape", is influenced by several cancer- and microenvironment-dependent factors. Senescence is a cellular program primed by cells in response to different pathophysiological stimuli, which is based on long-lasting cell cycle arrest and the secretion of numerous bioactive and inflammatory molecules. Because of this, cellular senescence is a potent immunomodulatory factor promptly recruiting immune cells and actively promoting tissue remodeling. In the context of cancer, these functions can lead to both cancer immunosurveillance and immunosuppression. In this review, the authors will discuss the role of senescence in cancer immunoediting, highlighting its context- and timing-dependent effects on the different three phases, describing how senescent cells promote immune cell recruitment for cancer cell elimination or sustain tumor microenvironment inflammation for immune escape. A potential contribution of senescent cells in cancer dormancy, as a mechanism of therapy resistance and cancer relapse, will be discussed with the final objective to unravel the immunotherapeutic implications of senescence modulation in cancer. [ABSTRACT FROM AUTHOR]

Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro‐survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions. [ABSTRACT FROM AUTHOR]

Vascular diseases pose major health challenges, and understanding their underlying molecular mechanisms is essential to advance therapeutic interventions. Cellular senescence, a hallmark of aging, is a cellular state characterized by cell-cycle arrest, a senescence-associated secretory phenotype macromolecular damage, and metabolic dysregulation. Vascular senescence has been demonstrated to play a key role in different vascular diseases, such as atherosclerosis, peripheral arterial disease, hypertension, stroke, diabetes, chronic venous disease, and venous ulcers. Even though cellular senescence was first described in 1961, significant gaps persist in comprehending the epigenetic mechanisms driving vascular senescence and its subsequent inflammatory response. Through a comprehensive analysis, we aim to elucidate these knowledge gaps by exploring the network of epigenetic alterations that contribute to vascular senescence. In addition, we describe the consequent inflammatory cascades triggered by these epigenetic modifications. Finally, we explore translational applications involving biomarkers of vascular senescence and the emerging field of senotherapy targeting this biological process. [ABSTRACT FROM AUTHOR]

Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we showed that CAFs with a myofibroblast phenotype released extracellular vesicles that transferred proteins to endothelial cells (ECs) that affected their interaction with immune cells. Mass spectrometry–based proteomics identified proteins transferred from CAFs to ECs, which included plasma membrane receptors. Using THY1 as an example of a transferred plasma membrane–bound protein, we showed that CAF-derived proteins increased the adhesion of a monocyte cell line to ECs. CAFs produced high amounts of matrix-bound EVs, which were the primary vehicles of protein transfer. Hence, our work paves the way for future studies that investigate how CAF-derived matrix-bound EVs influence tumor pathology by regulating the function of neighboring cancer, stromal, and immune cells. Editor's summary: Cancer-associated fibroblasts promote tumor growth, in part, by releasing extracellular vesicles, which can carry proteins to cells in the tumor microenvironment. Santi et al. investigated intercellular communication between endothelial cells in blood vessels and cancer-associated fibroblasts isolated from patients with breast cancer. Endothelial cells in vitro and in vivo took up proteins from extracellular vesicles, specifically matrix-bound vesicles, released by cancer-associated fibroblasts. Uptake of the membrane glycoprotein THY1 from cancer-associated fibroblasts increased the adhesion of monocytes to endothelial cells. Cancer-associated fibroblasts that released the most matrix-bound vesicles resembled myofibroblasts. Thus, identifying the proteins released by myofibroblast-like cancer-associated fibroblasts that alter endothelial cell function could yield potential targets for disrupting this intercellular communication. —Wei Wong [ABSTRACT FROM AUTHOR]

Endothelial cells line at the most inner layer of blood vessels. They act to control hemostasis, arterial tone/reactivity, wound healing, tissue oxygen, and nutrient supply. With age, endothelial cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profile. Endothelial senescence represents one of the earliest features of arterial ageing and contributes to many age-related diseases. Compared to those in arteries and veins, endothelial cells of the microcirculation exhibit a greater extent of heterogeneity. Microcirculatory endothelial senescence leads to a declined capillary density, reduced angiogenic potentials, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The heterogeneous phenotypes of microvascular endothelial cells in a particular vascular bed and across different tissues remain largely unknown. Accordingly, the mechanisms underlying macro- and micro-vascular endothelial senescence vary in different pathophysiological conditions, thus offering specific target(s) for therapeutic development of senolytic drugs. [ABSTRACT FROM AUTHOR]

The phenomenon of intercellular transfer of cellular material, including membranes, cytoplasm, and even organelles, has been observed for decades. The functional impact and molecular mechanisms of such transfer in the immune system remain largely elusive due to the absence of a robust in vivo model. Here, we introduce a new tumor mouse model, where tumor cells express the soluble ultra-bright fluorescent protein ZsGreen, which allows detection and measurement of intercellular transfer of cytoplasm from tumor cells to infiltrating immune cells. We found that in addition to various types of myeloid lineage cells, a large fraction of T regulatory cells and effector CD8 T cells acquire tumor material. Based on the distribution of tumor-derived ZsGreen, the majority of T cells integrate captured cytoplasm into their own, while most myeloid cells store tumor material in granules. Furthermore, scRNA-seq analysis revealed significant alterations in transcriptomes of T cells that acquired tumor cell cytoplasm, suggesting potential impact on T cell function. We identified that the participation of T cells in intercellular transfer requires cell-cell contact and is strictly dependent on the activation status of T lymphocytes. Finally, we propose to name the described phenomenon of intercellular transfer for tumor infiltrating T cells the "mosquito effect". [ABSTRACT FROM AUTHOR]

Challenges such as difficult wound healing, ischemic necrosis of skin flaps, and skin aging are prevalent in plastic surgery. Previous research has indeed suggested that these challenges in plastic surgery are often linked to cellular energy barriers. As the powerhouses of the cell, mitochondria play a critical role in sustaining cellular vitality and health. Fundamentally, issues like ischemic and hypoxic damage to organs and tissues, as well as aging, stem from mitochondrial dysfunction, which leads to a depletion of cellular energy. Hence, having an adequate number of high-quality, healthy mitochondria is vital for maintaining tissue stability and cell survival. In recent years, there has been preliminary exploration into the protective effects of mitochondrial transplantation against cellular damage in systems such as the nervous, cardiovascular, and respiratory systems. For plastic surgery, mitochondrial transplantation is an extremely advanced research topic. This review focuses on the novel applications and future prospects of mitochondrial transplantation in plastic surgery, providing insights for clinicians and researchers, and offering guidance to patients seeking innovative and effective treatment options., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field., (© 2024. Springer Nature Limited.)

Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis., (© 2024 Wiley Periodicals LLC.)

Trogocytosis is the intercellular transfer of membrane and membrane-associated proteins between cells. Trogocytosis is an underappreciated phenomenon that has historically routinely been dismissed as an artefact. With a greater understanding of the process and the implications it has on biological systems, trogocytosis has the potential to become a paradigm changer. The presence on a cell of molecules they don't endogenously express can alter the biological activity of the cell and could also lead to the acquisition of new functions. To better appreciate this phenomenon, it is important to understand how these intercellular membrane exchanges influence the function and activity of the donor and the recipient cells. In this chapter, we will examine how the molecules acquired by trogocytosis influence the biology of a variety of systems including mammalian fertilization, treatment of hemolytic disease of the newborn, viral and parasitic infections, cancer immunotherapy, and immune modulation., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The cellular stress and immunity cycle is a cornerstone of organismal homeostasis. Stress activates intracellular and intercellular communications within a tissue or organ to initiate adaptive responses aiming to resolve the origin of this stress. If such local measures are unable to ameliorate this stress, then intercellular communications expand toward immune activation with the aim of recruiting immune cells to effectively resolve the situation while executing tissue repair to ameliorate any damage and facilitate homeostasis. This cellular stress-immunity cycle is severely dysregulated in diseased contexts like cancer. On one hand, cancer cells dysregulate the normal cellular stress responses to reorient them toward upholding growth at all costs, even at the expense of organismal integrity and homeostasis. On the other hand, the tumors severely dysregulate or inhibit various components of organismal immunity, for example, by facilitating immunosuppressive tumor landscape, lowering antigenicity, and increasing T-cell dysfunction. In this review we aim to comprehensively discuss the basis behind tumoral dysregulation of cellular stress-immunity cycle. We also offer insights into current understanding of the regulators and deregulators of this cycle and how they can be targeted for conceptualizing successful cancer immunotherapy regimen., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)