Inter-organ Communication Research Articles

Steatotic hepatocyte-derived extracellular vesicles promote β-cell apoptosis and diabetes via microRNA-126a-3p.

Extracellular vesicles (EVs) have emerged as a unique mediator of interorgan communications, playing important roles in the pathophysiologic process of various diseases, including diabetes and other metabolic diseases. Here, we reported that the EVs released by steatotic hepatocytes exerted a detrimental effect on pancreatic β cells, leading to β-cell apoptosis and dysfunction. The effect was profoundly attributable to an up-regulation of miR-126a-3p in the steatotic hepatocyte-derived EVs. Accordingly, overexpression of miR-126a-3p promoted, whereas inhibition of miR-126a-3p prevented β-cell apoptosis, through a mechanism related to its target gene, insulin receptor substrate-2. Moreover, inhibition of miR-126a-3p by its specific antagomir was able to partially reverse the loss of β-cell mass and ameliorate hyperglycaemia in diabetic mice. Thus, the findings reveal a novel pathogenic role of steatotic hepatocyte-derived EVs, which mechanistically links nonalcoholic fatty liver disease to the development of diabetes.

1583-P: Dynamic Tracking and Identification of Liver-Specific Secretory Proteins in the Circulation of Live Mice

Secretory proteins are an essential component of interorgan communication networks that regulate animal physiology. Current approaches for identifying secretory proteins from specific cell and tissue types are largely limited to in vitro or ex vivo models which often fail to recapitulate in vivo biology. As such, there is mounting interest in developing in vivo analytical tools that can provide accurate information on the origin, identity, and spatiotemporal dynamics of secretory proteins. Here, we describe iSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which selectively labels proteins that transit through the classical secretory pathway via catalytic actions of Sec61b-TurboID, a proximity labeling enzyme anchored in the ER lumen. To validate iSLET in a whole-body system, we express iSLET in the mouse liver and demonstrate efficient labeling of liver secretory proteins which could be tracked and identified within circulating blood plasma. Furthermore, proteomic analysis of the labeled liver secretome enriched from liver iSLET mouse plasma is highly consistent with previous reports of liver secretory protein profiles. Taken together, iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets. Disclosure K.Kim: None. J.Suh: None. Funding National Research Foundation of Korea (2018R1A2A3075389, 2016M3A9B6902871, 2017K1A1A2013124, 2021R1A2C2007573, 2020R1C1C1013927); KAIST Key Research Institutes Project; Bio and Medical Technology Development Program (2019M3E5D3073104); Ministry of Science

Extracellular vesicles: pathogenic messengers and potential therapy for neonatal lung diseases.

Extracellular vesicles (EVs) are a heterogeneous group of nano-sized membranous structures increasingly recognized as mediators of intercellular and inter-organ communication. EVs contain a cargo of proteins, lipids and nucleic acids, and their cargo composition is highly dependent on the biological function of the parental cells. Their cargo is protected from the extracellular environment by the phospholipid membrane, thus allowing for safe transport and delivery of their intact cargo to nearby or distant target cells, resulting in modification of the target cell's gene expression, signaling pathways and overall function. The highly selective, sophisticated network through which EVs facilitate cell signaling and modulate cellular processes make studying EVs a major focus of interest in understanding various biological functions and mechanisms of disease. Tracheal aspirate EV-miRNA profiling has been suggested as a potential biomarker for respiratory outcome in preterm infants and there is strong preclinical evidence showing that EVs released from stem cells protect the developing lung from the deleterious effects of hyperoxia and infection. This article will review the role of EVs as pathogenic messengers, biomarkers, and potential therapies for neonatal lung diseases.

A phloem-localized Arabidopsis metacaspase (AtMC3) improves drought tolerance.

Increasing drought phenomena pose a serious threat to agricultural productivity. Although plants have multiple ways to respond to the complexity of drought stress, the underlying mechanisms of stress sensing and signaling remain unclear. The role of the vasculature, in particular the phloem, in facilitating inter-organ communication is critical and poorly understood. Combining genetic, proteomic and physiological approaches, we investigated the role of AtMC3, a phloem-specific member of the metacaspase family, in osmotic stress responses in Arabidopsis thaliana. Analyses of the proteome in plants with altered AtMC3 levels revealed differential abundance of proteins related to osmotic stress pointing into a role of the protein in water-stress-related responses. Overexpression of AtMC3 conferred drought tolerance by enhancing the differentiation of specific vascular tissues and maintaining higher levels of vascular-mediated transportation, while plants lacking the protein showed an impaired response to drought and inability to respond effectively to the hormone abscisic acid. Overall, our data highlight the importance of AtMC3 and vascular plasticity in fine-tuning early drought responses at the whole plant level without affecting growth or yield.

Response to oxidative stress of AML12 hepatocyte cells with knockout of methionine sulfoxide reductases

Methionine sulfoxide reductases are enzymes that reduce methionine oxidation in the cell. In mammals there are three B-type reductases that act on the R-diastereomer of methionine sulfoxide, and one A-type reductase (MSRA) that acts on the S-diastereomer. Unexpectedly, knocking out the four genes in the mouse protected from oxidative stresses such as ischemia-reperfusion injury and paraquat. To elucidate the mechanism by which lack of the reductases protects against oxidative stresses, we aimed to create a cell culture model with AML12 cells, a differentiated hepatocyte cell line. We employed CRISPR/Cas9 to create lines lacking the four individual reductases. All were viable and their susceptibility to oxidative stresses was the same as the parental strain. The triple knockout lacking all three methionine sulfoxide reductases B was also viable, but the quadruple knockout was lethal. We thus modeled the quadruple knockout mouse by creating an AML12 line lacking the three MSRB and heterozygous for the MSRA (Msrb3KO-Msra+/−). We measured the effect of ischemia-reperfusion on the various AML12 cell lines, using a protocol that modeled the ischemic phase by glucose and oxygen deprivation for 36 h followed by return of glucose and oxygen for 3 h as the reperfusion phase. This stress killed ∼50% of the parental line, an effect we chose to facilitate detection of either protective or deleterious changes in the knockout lines. Unlike the protection afforded the mouse, the knockout lines produced by CRISPR/Cas9 did not differ from the parental line in their response to ischemia-reperfusion injury or paraquat poisoning. In the mouse, inter-organ communication may be essential for protection induced by lack of methionine sulfoxide reductases.

From Obesity-Induced Low-Grade Inflammation to Lipotoxicity and Mitochondrial Dysfunction: Altered Multi-Crosstalk between Adipose Tissue and Metabolically Active Organs.

Obesity is a major risk factor for several metabolic diseases, including type 2 diabetes, hyperlipidemia, cardiovascular diseases, and brain disorders. Growing evidence suggests the importance of inter-organ metabolic communication for the progression of obesity and the subsequent onset of related disorders. This review provides a broad overview of the pathophysiological processes that from adipose tissue dysfunction leading to altered multi-tissue crosstalk relevant to regulating energy homeostasis and the etiology of obesity. First, a comprehensive description of the role of adipose tissue was reported. Then, attention was turned toward the unhealthy expansion of adipose tissue, low-grade inflammatory state, metabolic inflexibility, and mitochondrial dysfunction as root causes of systemic metabolic alterations. In addition, a short spot was devoted to iron deficiency in obese conditions and the role of the hepcidin-ferroportin relationship in the management of this issue. Finally, different classes of bioactive food components were described with a perspective to enhance their potential preventive and therapeutic use against obesity-related diseases.

Extracellular vesicle-mediated intercellular and interorgan crosstalk of pancreatic islet in health and diabetes.

Diabetes mellitus (DM) is a systemic metabolic disease with high mortality and morbidity. Extracellular vesicles (EVs) have emerged as a novel class of signaling molecules, biomarkers and therapeutic agents. EVs-mediated intercellular and interorgan crosstalk of pancreatic islets plays a crucial role in the regulation of insulin secretion of β-cells and insulin action in peripheral insulin target tissues, maintaining glucose homeostasis under physiological conditions, and it's also involved in pathological changes including autoimmune response, insulin resistance and β-cell failure associated with DM. In addition, EVs may serve as biomarkers and therapeutic agents that respectively reflect the status and improve function and viability of pancreatic islets. In this review, we provide an overview of EVs, discuss EVs-mediated intercellular and interorgan crosstalk of pancreatic islet under physiological and diabetic conditions, and summarize the emerging applications of EVs in the diagnosis and treatment of DM. A better understanding of EVs-mediated intercellular and interorgan communication of pancreatic islets will broaden and enrich our knowledge of physiological homeostasis maintenance as well as the development, diagnosis and treatment of DM.

Photosynthetic sucrose drives the lateral root clock in Arabidopsis seedlings

The development of plant roots is subject to control by light. Here, we show that, similar to monotonous root elongation, the periodic induction of lateral roots (LRs) depends on the activation by light of photomorphogenic and photosynthetic photoreceptors in the shoot in a hierarchical order. The prevailing belief is that the plant hormone auxin serves as a mobile signal transmitter, responsible for interorgan communication, including light-controlled shoot-to-root connections. Alternatively, it has been proposed that the transcription factor HY5 assumes the role as a mobile shoot-to-root signal transmitter. Here, we provide evidence that photosynthetic sucrose produced in the shoot acts as the long-distance signal carrier regulating the local, tryptophan-based biosynthesis of auxin in the LR generation zone of the primary root tip, where the LR clock controls the pace of LR initiation in an auxin-tunable manner. Synchronization of LR formation with primary root elongation allows the adjustment of overall root growth to the photosynthetic performance of the shoot and the maintenance of a constant LR density during light-dark changes in a variable light environment.

Insights into human kidney function from the study of Drosophila.

Biological and biomedical research using Drosophila melanogaster as a model organism has gained recognition through several Nobel prizes within the last 100years. Drosophila exhibits several advantages when compared to other in vivo models such as mice and rats, as its life cycle is very short, animal maintenance is easy and inexpensive and a huge variety of transgenic strains and tools are publicly available. Moreover, more than 70% of human disease-causing genes are highly conserved in the fruit fly. Here, we explain the use of Drosophila in nephrology research and describe two kidney tissues, Malpighian tubules and the nephrocytes. The latter are the homologous cells to mammalian glomerular podocytes and helped to provide insights into a variety of signaling pathways due to the high morphological similarities and the conserved molecular make-up between nephrocytes and podocytes. In recent years, nephrocytes have also been used to study inter-organ communication as links between nephrocytes and the heart, the immune system and the muscles have been described. In addition, other tissues such as the eye and the reproductive system can be used to study the functional role of proteins being part of the kidney filtration barrier.

Can exercise prevent the age‐related decline in adaptive homeostasis? Evidence across organisms and tissues

Can exercise prevent the age‐related decline in adaptive homeostasis? Evidence across organisms and tissues

Differential expression of adipocyte and myotube extracellular vesicle miRNA cargo in chronic binge alcohol-administered SIV-infected male macaques.

Our studies in chronic binge alcohol (CBA) -treated simian immunodeficiency virus (SIV)-infected macaques and in people living with HIV (PLWH) show significant alterations in metabolic homeostasis. CBA promotes a profibrotic phenotype in adipose tissue and skeletal muscle (SKM) and decreases adipose-derived stem cell and myoblast differentiation, making adipose and SKM potential drivers in metabolic dysregulation. Furthermore, we have shown that the differential expression of microRNAs (miRs) in SKM contributes to impaired myoblast differentiation potential. Beyond modulation of intracellular responses, miRs can be transported in extracellular vesicles (EVs) to mediate numerous cellular responses through intercellular and interorgan communication. This study tested the hypothesis that CBA alters concentration and miR cargo of EVs derived from adipocytes and myotubes isolated from SIV-infected male macaques. Fourteen male rhesus macaques received either CBA (2.5g/kg/day) or sucrose (VEH) for 14.5 months. Three months following the initiation of CBA/VEH, all animals were infected with SIVmac251 and 2.5 months later were initiated on antiretroviral therapy. SKM and adipose tissue samples were collected at the study endpoint (blood alcohol concentration=0mM). EVs were isolated by ultracentrifugation of myotube and adipocyte cell culture supernatant. Nanoparticle tracking revealed no differences in concentration or size of particles between VEH and CBA groups. Adipocyte-derived EVs from CBA animals showed decreased miR-let-7a expression (p=0.03). Myotube-derived EVs from CBA animals had decreased miR-16 (p=0.04) and increased miR-133a and miR-133b (both p=0.04) expression. These results indicate that CBA administration differentially regulates EV miR content but does not alter the number of EVs from adipocytes or myotubes. Future studies are warranted to determine the functional relevance of CBA-altered EV miR cargo and their role in intercellular and interorgan communication and metabolic dysregulation.

Extracellular Vesicles in Adipose Tissue Communication with the Healthy and Pathological Heart.

Adipose tissue and its diverse cell types constitute one of the largest endocrine organs. With multiple depot locations, adipose tissue plays an important regulatory role through paracrine and endocrine communication, particularly through the secretion of a wide range of bioactive molecules, such as nucleic acids, proteins, lipids or adipocytokines. Over the past several years, research has uncovered a myriad of interorgan communication signals mediated by small lipid-derived nanovesicles known as extracellular vesicles (EVs), in which secreted bioactive molecules are stably transported as cargo molecules and delivered to adjacent cells or remote organs. EVs constitute an essential part of the human adipose secretome, and there is a growing body of evidence showing the crucial implications of adipose-derived EVs in the regulation of heart function and its adaptative capacity. The adipose tissue modifications and dysfunction observed in obesity and aging tremendously affect the adipose-EV secretome, with important consequences for the myocardium. The present review presents a comprehensive analysis of the findings in this novel area of research, reports the key roles played by adipose-derived EVs in interorgan cross-talk with the heart and discusses their implications in physiological and pathological conditions affecting adipose tissue and/or the heart (pressure overload, ischemia, diabetic cardiomyopathy, etc.).

Role of the Microbiome in Gut-Heart-Kidney Cross Talk

Homeostasis is a prerequisite for health. When homeostasis becomes disrupted, dysfunction occurs. This is especially the case for the gut microbiota, which under normal conditions lives in symbiosis with the host. As there are as many microbial cells in and on our body as human cells, it is unlikely they would not contribute to health or disease. The gut bacterial metabolism generates numerous beneficial metabolites but also uremic toxins and their precursors, which are transported into the circulation. Barrier function in the intestine, the heart, and the kidneys regulates metabolite transport and concentration and plays a role in inter-organ and inter-organism communication via small molecules. This communication is analyzed from the perspective of the remote sensing and signaling theory, which emphasizes the role of a large network of multispecific, oligospecific, and monospecific transporters and enzymes in regulating small-molecule homeostasis. The theory provides a systems biology framework for understanding organ cross talk and microbe-host communication involving metabolites, signaling molecules, nutrients, antioxidants, and uremic toxins. This remote small-molecule communication is critical for maintenance of homeostasis along the gut-heart-kidney axis and for responding to homeostatic perturbations. Chronic kidney disease is characterized by gut dysbiosis and accumulation of toxic metabolites. This slowly impacts the body, affecting the cardiovascular system and contributing to the progression of kidney dysfunction, which in its turn influences the gut microbiota. Preserving gut homeostasis and barrier functions or restoring gut dysbiosis and dysfunction could be a minimally invasive way to improve patient outcomes and quality of life in many diseases, including cardiovascular and kidney disease.

Increased Risk of Cardiovascular Complications in Chronic Kidney Disease: Introduction to a Compendium.

Increased Risk of Cardiovascular Complications in Chronic Kidney Disease: Introduction to a Compendium.

First person – Rebeka Popovic and Yizhou Yu

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Rebeka Popovic and Yizhou Yu are co-first authors on ‘ Upregulation of Tribbles decreases body weight and increases sleep duration’, published in DMM. Rebeka conducted the research described in this article while a PhD student in Dr Luis Miguel Martins’ lab at the University of Cambridge, Cambridge, UK. Her PhD investigated mechanisms of neurodegeneration, with a focus on endoplasmic reticulum stress and mitochondrial dysfunction, as well as inter-organ communication in disease. She is now a postdoc in the lab of Prof. Fiona Ducotterd at the Drug Discovery Institute at University College London, London, UK, exploring new therapeutic targets for the treatment of neurodegenerative diseases. Yizhou is a PhD student in the lab of Dr Luis Miguel Martins at the University of Cambridge, Cambridge, UK. His research involves combining computational biology and wet-lab techniques to understand the genetic and environmental causes of age-related diseases.

Fat-to-heart crosstalk in health and disease.

According to the latest World Health Organization statistics, cardiovascular disease (CVD) is one of the leading causes of death globally. Due to the rise in the prevalence of major risk factors, such as diabetes mellitus and obesity, the burden of CVD is expected to worsen in the decades to come. Whilst obesity is a major and consistent risk factor for CVD, the underlying pathological molecular communication between peripheral fat depots and the heart remains poorly understood. Adipose tissue (AT) is a major endocrine organ in the human body, with composite cells producing and secreting hormones, cytokines, and non-coding RNAs into the circulation to alter the phenotype of multiple organs, including the heart. Epicardial AT (EAT) is an AT deposit that is in direct contact with the myocardium and can therefore influence cardiac function through both mechanical and molecular means. Moreover, resident and recruited immune cells comprise an important adipose cell type, which can create a pro-inflammatory environment in the context of obesity, potentially contributing to systemic inflammation and cardiomyopathies. New mechanisms of fat-to-heart crosstalk, including those governed by non-coding RNAs and extracellular vesicles, are being investigated to deepen the understanding of this highly common risk factor. In this review, molecular crosstalk between AT and the heart will be discussed, with a focus on endocrine and paracrine signaling, immune cells, inflammatory cytokines, and inter-organ communication through non-coding RNAs.

Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice.

Dysregulation of estrogen receptor alpha (ERα) has been linked with increased metabolic and cardiovascular disease risk. Here, we generate and characterize cardiomyocyte-specific ERα knockout (ERαHKO) mice to assess the role of ERα in the heart. The most striking phenotype was obesity in female ERαHKO but not male ERαHKO mice. Female ERαHKO mice showed cardiac dysfunction, mild glucose and insulin intolerance and reduced ERα gene expression in skeletal muscle and white adipose tissue. Transcriptomic, proteomic, lipidomic and metabolomic analyses revealed evidence of contractile and/or metabolic dysregulation in heart, skeletal muscle and white adipose tissue. We show that heart-derived extracellular vesicles from female ERαHKO mice contain a distinct proteome associated with lipid and metabolic regulation, and have the capacity to metabolically reprogram the target skeletal myocyte proteome with functional impacts on glycolytic capacity and reserve. This multi-omics study uncovers a cardiac-initiated and sex-specific cardiometabolic phenotype regulated by ERα and provides insights into extracellular vesicle-mediated interorgan communication.

New insights into the inter-organ crosstalk mediated by ChREBP.

Carbohydrate response element binding protein (ChREBP) is a glucose responsive transcription factor recognized by its critical role in the transcriptional control of glycolysis and de novo lipogenesis. Substantial advances in the field have revealed novel ChREBP functions. Indeed, due to its actions in different tissues, ChREBP modulates the inter-organ communication through secretion of peptides and lipid factors, ensuring metabolic homeostasis. Dysregulation of these orchestrated interactions is associated with development of metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Here, we recapitulate the current knowledge about ChREBP-mediated inter-organ crosstalk through secreted factors and its physiological implications. As the liver is considered a crucial endocrine organ, we will focus in this review on the role of ChREBP-regulated hepatokines. Lastly, we will discuss the involvement of ChREBP in the progression of metabolic pathologies, as well as how the impairment of ChREBP-dependent signaling factors contributes to the onset of such diseases.

Intra-pituitary follicle-stimulating hormone signaling regulates hepatic lipid metabolism in mice

Inter-organ communication is a major hallmark of health and is often orchestrated by hormones released by the anterior pituitary gland. Pituitary gonadotropes secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to regulate gonadal function and control fertility. Whether FSH and LH also act on organs other than the gonads is debated. Here, we find that gonadotrope depletion in adult female mice triggers profound hypogonadism, obesity, glucose intolerance, fatty liver, and bone loss. The absence of sex steroids precipitates these phenotypes, with the notable exception of fatty liver, which results from ovary-independent actions of FSH. We uncover paracrine FSH action on pituitary corticotropes as a mechanism to restrain the production of corticosterone and prevent hepatic steatosis. Our data demonstrate that functional communication of two distinct hormone-secreting cell populations in the pituitary regulates hepatic lipid metabolism.

Transcriptomics Dissection of Calorie Restriction and Exercise Training in Brown Adipose Tissue and Skeletal Muscle

Calorie restriction (CR) and exercise training (EX) are two critical lifestyle interventions for the prevention and treatment of metabolic diseases, such as obesity and diabetes. Brown adipose tissue (BAT) and skeletal muscle are two important organs for the generation of heat. Here, we undertook detailed transcriptional profiling of these two thermogenic tissues from mice treated subjected to CR and/or EX. We found transcriptional reprogramming of BAT and skeletal muscle as a result of CR but little from EX. Consistent with this, CR induced alterations in the expression of genes encoding adipokines and myokines in BAT and skeletal muscle, respectively. Deconvolution analysis showed differences in the subpopulations of myogenic cells, mesothelial cells and endogenic cells in BAT and in the subpopulations of satellite cells, immune cells and endothelial cells in skeletal muscle as a result of CR or EX. NicheNet analysis, exploring potential inter-organ communication, indicated that BAT and skeletal muscle could mutually regulate their fatty acid metabolism and thermogenesis through ligands and receptors. These data comprise an extensive resource for the study of thermogenic tissue molecular responses to CR and/or EX in a healthy state.