Transfer Of Organelles Research Articles

Transplanted human photoreceptors transfer cytoplasmic material but not to the recipient mouse retina

BackgroundThe discovery of material transfer between transplanted and host mouse photoreceptors has expanded the possibilities for utilizing transplanted photoreceptors as potential vehicles for delivering therapeutic cargo. However, previous research has not directly explored the capacity for human photoreceptors to engage in material transfer, as human photoreceptor transplantation has primarily been investigated in rodent models of late-stage retinal disease, which lack host photoreceptors.MethodsIn this study, we transplanted human stem-cell derived photoreceptors purified from human retinal organoids at different ontological ages (weeks 10, 14, or 20) into mouse models with intact photoreceptors and assessed transfer of human proteins and organelles to mouse photoreceptors.ResultsUnexpectedly, regardless of donor age or mouse recipient background, human photoreceptors did not transfer material in the mouse retina, though a rare subset of donor cells (< 5%) integrated into the mouse photoreceptor cell layer. To investigate the possibility that a species barrier impeded transfer, we used a flow cytometric assay to examine material transfer in vitro. Interestingly, dissociated human photoreceptors transferred fluorescent protein with each other in vitro, yet no transfer was detected in co-cultures of human and mouse photoreceptors, suggesting that material transfer is species specific.ConclusionsWhile xenograft models are not a tractable system to study material transfer of human photoreceptors, these findings demonstrate that human retinal organoid-derived photoreceptors are competent donors for material transfer and thus may be useful to treat retinal degenerative disease.

Tunneling nanotubes and tumor microtubes-Emerging data on their roles in intercellular communication and pathophysiology: Summary of an International FASEB Catalyst Conference October 2023.

In the past decade, there has been a steady rise in interest in studying novel cellular extensions and their potential roles in facilitating human diseases, including neurologic diseases, viral infectious diseases, cancer, and others. One of the exciting new aspects of this field is improved characterization and understanding of the functions and potential mechanisms of tunneling nanotubes (TNTs), which are actin-based filamentous protrusions that are structurally distinct from filopodia. TNTs form and connect cells at long distance and serve as direct conduits for intercellular communication in a wide range of cell types in vitro and in vivo. More researchers are entering this field and investigating the role of TNTs in mediating cancer cell invasion and drug resistance, cellular transfer of proteins, RNA or organelles, and intercellular spread of infectious agents, such as viruses, bacteria, and prions. Even further, the elucidation of highly functional membrane tubes called "tumor microtubes" (TMs) in incurable gliomas has further paved a new path for understanding how and why the tumor type is highly invasive at the cellular level and also resistant to standard therapies. Due to the wide-ranging and rapidly growing applicability of TNTs and TMs in pathophysiology across the spectrum of biology, it has become vital to bring researchers in the field together to discuss advances and the future of research in this important niche of protrusion biology.

Mesenchymal Stem Cell Applications in Graft Versus Host Disease

Allogeneic hematopoietic stem cell transplantation stands as a promising cure for a variety of diseases. However, the potential of acute or chronic graft-versus-host disease (GvHD), which leads to significant morbidity and mortality, remains a cause for concern. GvHD occurs due to the complex interactions of immune cells from the graft and the host cells. Despite the existence of prophylactic treatments, GvHD may still occur, and the resistance to conventional therapies necessitates novel approaches and treatments. Mesenchymal stem cells, which are pluripotent stem cells capable of self-renewal and multilineage differentiation, have gained attention for their low immunogenicity and ability to be sourced from various origins. They have shown promise as therapeutic tools for the cell-based treatment of inflammatory, immune-mediated, and degenerative diseases owing to their remarkable abilities in immunomodulation, immunosuppression, and tissue regeneration. In GvHD, MSCs have demonstrated therapeutic potential through paracrine activity and organelle transfer via nanotubes, microvesicles, or exosomes. The emergence of MSCs as a treatment for severe steroid-resistant GvHD gained attention in the early 2000s. While initial studies have demonstrated encouraging results in the use of MSCs for the prevention of GvHD, there is still a need for further investigation. Therefore, in this current review, we aim to delve deeper into MSC’s features and their clinical applications in the case of GvHD treatment.

A role for tunneling nanotubes in virus spread.

Tunneling nanotubes (TNTs) are actin-rich intercellular conduits that mediate distant cell-to-cell communication and enable the transfer of various cargos, including proteins, organelles, and virions. They play vital roles in both physiological and pathological processes. In this review, we focus on TNTs in different types of viruses, including retroviruses such as HIV, HTLV, influenza A, herpesvirus, paramyxovirus, alphavirus and SARS-CoV-2. We summarize the viral proteins responsible for inducing TNT formation and explore how these virus-induced TNTs facilitate intercellular communication, thereby promoting viral spread. Furthermore, we highlight other virus infections that can induce TNT-like structures, facilitating the dissemination of viruses. Moreover, TNTs promote intercellular spread of certain viruses even in the presence of neutralizing antibodies and antiviral drugs, posing significant challenges in combating viral infections. Understanding the mechanisms underlying viral spread via TNTs provides valuable insights into potential drug targets and contributes to the development of effective therapies for viral infections.

Tunneling nanotube-transmitted mechanical signal and its cellular response

Tunneling nanotubes (TNTs) are elastic tubular structures that physically link cells, facilitating the intercellular transfer of organelles, chemical signals, and electrical signals. Despite TNTs serving as a multifunctional pathway for cell-cell communication, the transmission of mechanical signals through TNTs and the response of TNT-connected cells to these forces remain unexplored. In this study, external mechanical forces were applied to induce TNT bending between rat kidney (NRK) cells using micromanipulation. These forces, transmitted via TNTs, induced reduced curvature of the actin cortex and increased membrane tension at the TNT-connected sites. Additionally, TNT bending results in an elevation of intracellular calcium levels in TNT-connected cells, a response attenuated by gadolinium ions, a non-selective mechanosensitive calcium channel blocker. The degree of TNT deflection positively correlated with decreased actin cortex curvature and increased calcium levels. Furthermore, stretching TNT due to the separation of TNT-connected cells resulted in decreased actin cortex curvature and increased intracellular calcium in TNT-connected cells. The levels of these cellular responses depended on the length changes of TNTs. Moreover, TNT connections influence cell migration by regulating cell rotation, which involves the activation of mechanosensitive calcium channels. In conclusion, our study revealed the transmission of mechanical signals through TNTs and the subsequent responses of TNT-connected cells, highlighting a previously unrecognized communication function of TNTs. This research provides valuable insights into the role of TNTs in long-distance intercellular mechanical signaling.

Increasing Intercellular Communication and Directional Organelle Transfer in Oyster Hemocytes under Copper Stress

Increasing Intercellular Communication and Directional Organelle Transfer in Oyster Hemocytes under Copper Stress

Shotgun Proteomics of Co-Cultured Leukemic and Bone Marrow Stromal Cells from Different Species as a Preliminary Approach to Detect Intercellular Protein Transfer

Cellular interactions within the bone marrow microenvironment modulate the properties of subsets of leukemic cells leading to the development of drug-resistant phenotypes. The intercellular transfer of proteins and organelles contributes to this process but the set of transferred proteins and their effects in the receiving cells remain unclear. This study aimed to detect the intercellular protein transfer from mouse bone marrow stromal cells (OP9 cell line) to human T-lymphoblasts (CCRF-CEM cell line) using nanoLC-MS/MS-based shotgun proteomics in a 3D co-culture system. After 24 h of co-culture, 1513 and 67 proteins from human and mouse origin, respectively, were identified in CCRF-CEM cells. The presence of mouse proteins in the human cell line, detected by analyzing the differences in amino acid sequences of orthologous peptides, was interpreted as the result of intercellular transfer. The transferred proteins might have contributed to the observed resistance to vincristine, methotrexate, and hydrogen peroxide in the co-cultured leukemic cells. Our results suggest that shotgun proteomic analyses of co-cultured cells from different species could be a simple option to get a preliminary survey of the proteins exchanged among interacting cells.

BIOGENIC AND ANTHROPOGENIC MAGNETIC NANOPARTICLES IN THE PHLOEM SIEVE TUBES OF PLANTS

The samples of leaves and roots of Nicotiana tabacum, the stems and tubers of Solanum tuberosum and the stems of pea Pisum sativum were examined by scanning probe microscopy in atomic force and magnetic force modes after cultivation without and with addition of magnetite nanoparticles in soil. Chains of both biogenic and anthropogenic magnetic nanoparticles are detected in the wall of the phloem sieve tubes i.e., the vascular tissue of plants. Such a localization of biogenic magnetic nanoparticles supports the idea that the chains of magnetic nanoparticles in different organs of plants have common metabolic functions. Stray gradient magnetic fields about several thousand Oe, which are created by chains of both biogenic and anthropogenic magnetic nanoparticles, can significantly affect the metabolic processes through the influence on mass transfer of vesicles, granules, organelles and other components. In view of the results of this investigation, both BMNs and anthropogenic magnetite nanoparticles chains can significantly affect the processes of mass transfer of vesicles, organelles, structural elements of the membrane and others components because they create stray magnetic fields and gradient magnetic forces.

Mesenchymal stromal cell therapy for chronic lung diseases: experimental and clinical evidence

Introduction Cell therapy has emerged as an alternative option for chronic lung diseases with the highest rates of morbidity and mortality rates worldwide. Areas covered This review addresses the definition of mesenchymal stromal cells (MSCs), their properties, mechanisms of action, as well as preclinical and clinical studies that have used cell therapy in chronic lung diseases such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, and silicosis. Ongoing clinical trials are also presented. Expert opinion Experimental evidence has shown that MSCs have immunomodulatory and regenerative properties that could rescue impaired lung function and histoarchitecture. Their beneficial effects have been mainly associated with their ability to communicate with target cells through the secretion of soluble mediators and extracellular vesicles or even through transfer of organelles (e.g. mitochondria). MSC-derived conditioned medium, extracellular vesicles and mitochondria induce beneficial effects in selected scenarios. The initial results in clinical trials were modest compared with the experimental results, therefore researchers were encouraged to move from bedside back to bench to develop new strategies able to potentiate the effects of MSCs.

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury.

Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.

Mechanical properties of tunneling nanotube and its mechanical stability in human embryonic kidney cells.

Tunneling nanotubes (TNTs) are thin membrane tubular structures that interconnect physically separated cells. Growing evidence indicates that TNTs play unique roles in various diseases by facilitating intercellular transfer of signaling and organelles, suggesting TNTs as a potential target for disease treatment. The efficiency of TNT-dependent communication is largely determined by the number of TNTs between cells. Though TNTs are physically fragile structures, the mechanical properties of TNTs and the determinants of their mechanical stability are still unclear. Here, using atomic force microscope (AFM) and microfluidic techniques, we investigated the mechanical behavior and abundance of TNTs in human embryonic kidney (HEK293) cells upon the application of forces. AFM measurements demonstrate that TNTs are elastic structures with an apparent spring constant of 79.1 ± 16.2 pN/μm. The stiffness and membrane tension of TNTs increase by length. TNTs that elongate slower than 0.5 μm/min display higher mechanical stability, due to the growth rate of F-actin inside TNTs being limited at 0.26 μm/min. Importantly, by disturbing the cytoskeleton, membrane, or adhesion proteins of TNTs, we found that F-actin and cadherin connection dominantly determines the tensile strength and flexural strength of TNTs respectively. It may provide new clues for screening TNT-interfering drugs that alter the stability of TNTs.

Wheat Antipodal Cells with Polytene Chromosomes in the Embryo Sac Are Key to Understanding the Formation of Grain in Cereals.

Simple SummaryThe present work is devoted to the features of antipodal cells at the early stages of wheat seed development, ensuring the formation and protection of a full-fledged grain. Using the methods of cell and molecular biology, changes in the structure of these cells and their components during active functioning and death are shown. For the first time, data on the expression of some genes confirming the functions of antipodal cells were obtained. The characteristic features of cells at the stages of death were revealed. The data obtained indicate the key role of antipodal cells in the process of grain maturation and subsequently allow us to identify substances that ensure the formation of tissue, which is the food of the whole world.The ultrastructure of antipodal cells of the Triticum aestivum embryo sac was studied at different stages of differentiation and programmed cell death. The importance of cell function in the antipodal complex is evidenced by the fact that it is fully formed before double fertilization, past the stages of proliferation of three initial cells, and several rounds of genome endoreduplication during differentiation. In this study, we showed that the actively synthesizing organelles, the granular reticulum, and Golgi apparatus, alter their structure during differentiation and death. The polymorphism of the shape of the mitochondria and plastids was demonstrated. For the first time, the actin filaments of the cytoskeleton and numerous multivesicular bodies associated with the plasma membrane were detected in the cytoplasm. The transfer of cytoplasm and organelles between antipodal cells and into the coenocyte of the endosperm was confirmed. DNA breaks and the release of cytochrome c at various stages of death were revealed. To understand the function of the antipodal cells, a quantitative PCR analysis of the expression of wheat genes involved in protective, antistress, and metabolic processes was carried out. We found that gene expression in the antipodal cell fraction was increased compared with that in the whole embryo sac. On the basis of the data, we assume that antipodal cells produce both nutrients and numerous antistress factors that ensure the normal development of the endosperm of the grain, which, in turn, further ensures the development of the embryo.

Abstract 4 Umbilical Cord-Derived Mesenchymal Stromal Cells Suppress Neuroinflammation and Promote Remyelination in the Spinal Cord

IntroductionMesenchymal stromal cells (MSCs) are one of the most widely tested cell therapies due to their ability to suppress inflammation. Demyelinating diseases of the central nervous system (CNS) are commonly accompanied by neuroinflammation, including infiltrating proinflammatory leukocytes and activation of resident macrophages (microglia and border-associated macrophages in the meninges). The precise mechanism of how MSCs suppress neuroinflammation is unclear; however, we recently described a novel pathway where MSCs physically interact with macrophages to reprogram the immune response through the transfer of a cytoplasmic organelle called a processing body (p-body).ObjectiveWe set out to study how human umbilical cord tissue-derived MSCs interact with CNS microglia and border macrophages to protect in a mouse model of spinal cord demyelination.MethodsWe manufactured several MSC lines under GMP conditions and tested their ability to interact with CNS macrophages and promote remyelination in multiple preclinical assays. To determine if p-bodies are critical for these steps, we depleted p-bodies using CRISPR/Cas9 targeting to DDX6. To test for effects on acute demyelination, we injected lysophosphatidylcholine (LPC) into the spinal cord or added LPC to organotypic cerebellar slice cultures. To test direct effects on microglia activation, we treated primary microglia or a microglia cell line with lipopolysaccharide.ResultsWe determined that MSC promoted remyelination in the spinal cord and that this was dependent on p-bodies. MSC directly contacted CNS macrophages and inhibited their activation. Using primary microglia and a microglia cell line, we determined that MSCs suppress the release of proinflammation cytokines, IL-6, and TNF.DiscussionWe determined that MSCs suppress microglial cell activation and enhance remyelination of the spinal cord. Our study offers insight into a novel mechanism about how MSCs can alter the immune response via transferring p-bodies and enhance remyelination in CNS. Furthermore, our results may lead to a quick and simple potency assay to establish the efficacy of MSCs for suppressing neuroinflammation.

Role of pericytes in blood–brain barrier preservation during ischemia through tunneling nanotubes

Crosstalk mechanisms between pericytes, endothelial cells, and astrocytes preserve integrity and function of the blood-brain-barrier (BBB) under physiological conditions. Long intercellular channels allowing the transfer of small molecules and organelles between distant cells called tunneling nanotubes (TNT) represent a potential substrate for energy and matter exchanges between the tripartite cellular compartments of the BBB. However, the role of TNT across BBB cells under physiological conditions and in the course of BBB dysfunction is unknown. In this work, we analyzed the TNT’s role in the functional dialog between human brain endothelial cells, and brain pericytes co-cultured with human astrocytes under normal conditions or after exposure to ischemia/reperfusion, a condition in which BBB breakdown occurs, and pericytes participate in the BBB repair. Using live time-lapse fluorescence microscopy and laser-scanning confocal microscopy, we found that astrocytes form long TNT with pericytes and endothelial cells and receive functional mitochondria from both cell types through this mechanism. The mitochondrial transfer also occurred in multicellular assembloids of human BBB that reproduce the three-dimensional architecture of the BBB. Under conditions of ischemia/reperfusion, TNT formation is upregulated, and astrocytes exposed to oxygen-glucose deprivation were rescued from apoptosis by healthy pericytes through TNT-mediated transfer of functional mitochondria, an effect that was virtually abolished in the presence of TNT-destroying drugs. The results establish a functional role of TNT in the crosstalk between BBB cells and demonstrate that TNT-mediated mitochondrial transfer from pericytes rescues astrocytes from ischemia/reperfusion-induced apoptosis. Our data confirm that the pericytes might play a pivotal role in preserving the structural and functional integrity of BBB under physiological conditions and participate in BBB repair in brain diseases.

Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy

ABSTRACT Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants of DN. However, the underlying mechanisms of podocyte injury remain poorly understood. The cytosolic protein TNFAIP2/M-Sec is required for tunneling nanotubes (TNTs) formation, which are membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 and form TNTs, but the potential relevance of the TNFAIP2-TNT system in DN is unknown. We studied TNFAIP2 expression in both human and experimental DN and the renal effect of tnfaip2 deletion in streptozotocin-induced DN. Moreover, we explored the role of the TNFAIP2-TNT system in podocytes exposed to diabetes-related insults. TNFAIP2 was overexpressed by podocytes in both human and experimental DN and exposre of podocytes to high glucose and AGEs induced the TNFAIP2-TNT system. In diabetic mice, tnfaip2 deletion exacerbated albuminuria, renal function loss, podocyte injury, and mesangial expansion. Moreover, blockade of the autophagic flux due to lysosomal dysfunction was observed in diabetes-injured podocytes both in vitro and in vivo and exacerbated by tnfaip2 deletion. TNTs allowed autophagosome and lysosome exchange between podocytes, thereby ameliorating AGE-induced lysosomal dysfunction and apoptosis. This protective effect was abolished by tnfaip2 deletion, TNT inhibition, and donor cell lysosome damage. By contrast, Tnfaip2 overexpression enhanced TNT-mediated transfer and prevented AGE-induced autophagy and lysosome dysfunction and apoptosis. In conclusion, TNFAIP2 plays an important protective role in podocytes in the context of DN by allowing TNT-mediated autophagosome and lysosome exchange and may represent a novel druggable target. Abbreviations: AGEs: advanced glycation end products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: diabetic nephropathy; FSGS: focal segmental glomerulosclerosis; HG: high glucose; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: tumor necrosis factor, alpha-induced protein 2; TNTs: tunneling nanotubes; WT: wild type.

TAMI-51. HORIZONTAL MITOCHONDRIAL TRANSFER FROM THE TUMOR MICROENVIRONMENT TO GLIOBLASTOMA INCREASES TUMORIGENICITY

Abstract Communication between glioblastoma (GBM) and its microenvironment facilitates tumor growth and therapeutic resistance, and is facilitated through a variety of mechanisms. Organelle transfer between cells was recently observed, including mitochondria transfer from astrocytes to neurons after ischemic stroke. Given the dependence of GBM on microenvironmental interactions, we hypothesized that mitochondria transfer from tumor microenvironment to GBM cells could occur and affect metabolism and tumorigenicity. We interrogated this in vivo by establishing intracranial GBM tumors in mito::mKate2 mice (with trackable fluorescent mitochondria) using syngeneic GFP-expressing tumor cells (SB28 and GL261 models). We also cultured stromal cell types from mito::mKate2 mice with tumor cells, enabling sorting of tumor cells with and without exogenous mitochondria. Confocal microscopy revealed horizontal transfer of mKate2+ mitochondria from mouse cells to implanted GBM cells in vivo and was confirmed by flow cytometry where 20-40% of GBM cells acquired exogenous mitochondria. Transfer was negligible in wildtype mice transplanted with mito::mKate2 bone marrow cells, suggesting that brain-resident cells were the main donors. In vitro, astrocytes and microglia exhibited 5 to 10-fold higher mitochondrial transfer rate than bone-marrow derived macrophages. Seahorse metabolic profiling revealed that GBM cells with mKate2+ mitochondria had 40% lower respiratory reserve compared to cells without exogenous mitochondria. Median survival of mice implanted with SB28 that acquired mitochondria was significantly shorter and in vivo limiting dilution confirmed the frequency of tumor-initiating cells was 3-fold higher in SB28 cells with exogenous mitochondria. Our data indicate that horizontal mitochondrial transfer from brain-resident glia to mouse GBM tumors alters tumor cell metabolism and increases their tumorigenicity. Ongoing studies are assessing gene expression in GBM cells acquiring exogenous mitochondria; validating findings in human specimens; and screening for transfer inhibitor drugs. Horizontal mitochondrial transfer represents a foundational tumor microenvironment interaction contributing to glioblastoma plasticity, and is likely to inform next-generation treatment strategies.

Mechanisms of stem cells action: reality and hypotheses

Despite the long history of stem cells studying, the mechanisms of their action are still not fully understood. A classic example is the described non-hematological effect of hematopoietic stem cells (HSC), presumably due to the ability to transdifferentiation and cell fusion. The focus of clinical application in the field of regenerative medicine is mesenchymal stromal cells (MSC), and the understanding of the ways of implementfnion of their regenerative potential has evolved significantly. MSC were discovered and described as a structural unit of the HSC niche responsible for the repair of connective tissue through differentiation. However, it later turned out that they are a regulator of various processes in the body as a whole. These processes include anti-inflammatory, antifibrotic, and immunomodulatory effects, which are realized in various ways. Among these pathways, the paracrine mechanism has already been identified – the release of various growth factors, exosomes and microvesicles, the mechanism of direct transfer of mitochondria and other cellular organelles from cell to cell using tunneling nanotubes, the mechanism of efferocytosis. One of the latest discoveries in this field was the immunomodulatory effect of apoptotic MSC.In general, the study of the stem cells mechanisms of action is a living, developing field of science in which the last word will not be said soon.

Connecting different heart diseases through intercellular communication.

ABSTRACTWell-orchestrated intercellular communication networks are pivotal to maintaining cardiac homeostasis and to ensuring adaptative responses and repair after injury. Intracardiac communication is sustained by cell–cell crosstalk, directly via gap junctions (GJ) and tunneling nanotubes (TNT), indirectly through the exchange of soluble factors and extracellular vesicles (EV), and by cell–extracellular matrix (ECM) interactions. GJ-mediated communication between cardiomyocytes and with other cardiac cell types enables electrical impulse propagation, required to sustain synchronized heart beating. In addition, TNT-mediated organelle transfer has been associated with cardioprotection, whilst communication via EV plays diverse pathophysiological roles, being implicated in angiogenesis, inflammation and fibrosis. Connecting various cell populations, the ECM plays important functions not only in maintaining the heart structure, but also acting as a signal transducer for intercellular crosstalk. Although with distinct etiologies and clinical manifestations, intercellular communication derailment has been implicated in several cardiac disorders, including myocardial infarction and hypertrophy, highlighting the importance of a comprehensive and integrated view of complex cell communication networks. In this review, I intend to provide a critical perspective about the main mechanisms contributing to regulate cellular crosstalk in the heart, which may be considered in the development of future therapeutic strategies, using cell-based therapies as a paradigmatic example. This Review has an associated Future Leader to Watch interview with the author.

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.

Besides being powerhouses of the cell, mitochondria released into extracellular space act as intercellular signaling. Mitochondria and their components mediate cell-to-cell communication in free form or embedded in a carrier. The pathogenesis of cardiovascular disease is complex, which shows close relationship with inflammation and metabolic abnormalities. Since mitochondria sustain optimal function of the heart, extracellular mitochondria are emerging as a key regulator in the development of cardiovascular disease. In this review, we provide recent findings in the presence and forms of mitochondria transfer between cells, as well as the effects of these mitochondria on vascular inflammation and ischemic myocardium. Mitochondrial transplantation is a novel treatment paradigm for patients suffering from acute cardiovascular accident and challenges the traditional methods of mitochondria isolation.

Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis.

Macrophages are involved in almost every aspect of biological systems and include development, homeostasis and repair. Mesenchymal stem cells (MSCs) have good clinical application prospects due to their ability to regulate adaptive and innate immune cells, particularly macrophages, and they have been used successfully for many immune disorders, including inflammatory bowel disease (IBD), acute lung injury, and wound healing, which have been reported as macrophage-mediated disorders. In the present review, we focus on the interaction between MSCs and macrophages and summarize their methods of interaction and communication, such as cell-to-cell contact, soluble factor secretion, and organelle transfer. In addition, we discuss the roles of MSC-macrophage crosstalk in the development of disease and maintenance of homeostasis of inflammatory microenvironments. Finally, we provide optimal strategies for applications in immune-related disease treatments.