Exosomes in Mesenchymal Stem Cells,a New Therapeutic Strategy for Cardiovascular Diseases?

Cardiovascular diseases (CVDs) are still a major cause of people deaths worldwide, and mesenchymal stem cells (MSCs) transplantation holds great promise due to its capacity to differentiate into cardiovascular cells and secrete protective cytokines, which presents an important mechanism of MSCs therapy for CVDs. Although the capability of MSCs to differentiate into cardiomyocytes (CMCs), endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) has been well recognized in massive previous experiments both in vitro and in vivo, low survival rate of transplanted MSCs in recipient hearts suggests that therapeutic effects of MSCs transplantation might be also correlated with other underlying mechanisms. Notably, recent studies uncovered that MSCs were able to secret cholesterol-rich, phospholipid exosomes which were enriched with microRNAs (miRNAs). The released exosomes from MSCs acted on hearts and vessels, and then exerted anti-apoptosis, cardiac regeneration, anti-cardiac remodeling, anti-inflammatory effects, neovascularization and anti-vascular remodeling, which are considered as novel molecular mechanisms of therapeutic potential of MSCs transplantation. Here we summarized recent advances about the role of exosomes in MSCs therapy for CVDs, and discussed exosomes as a novel approach in the treatment of CVDs in the future.     

Spinal Cord Injury: Animal Models,Imaging Tools and the Treatment Strategies

Spinal cord injury (SCI) often leads to irreversible neuro-degenerative changes with life-long consequences. While there is still no effective therapy available, the results of past research have led to improved quality of life for patients suffering from partial or permanent paralysis. In this review we focus on the need, importance and the scientific value of experimental animal models simulating SCI in humans. Furthermore, we highlight modern imaging tools determining the location and extent of spinal cord damage and their contribution to early diagnosis and selection of appropriate treatment. Finally, we focus on available cellular and acellular therapies and novel combinatory approaches with exosomes and active biomaterials. Here we discuss the efficacy and limitations of adult mesenchymal stem cells which can be derived from bone marrow, adipose tissue or umbilical cord blood and its Wharton’s jelly. Special attention is paid to stem cell-derived exosomes and smart biomaterials due to their special properties as a delivery system for proteins, bioactive molecules or even genetic material.

     

Ageing and mesenchymal stem cells derived exosomes: Molecular insight and challenges

Ageing induces a great risk factor that participates in progressing various degenerative diseases morbidities. The main characteristic of ageing is the failure in maintaining homeostasis in the organs with a cellular senescence. Senescence is characterized by reduced cell growth, evade cellular death, and acquiring a senescence‐associated secretory phenotype (SASP). Mesenchymal stem cells (MSCs) are advantageous cells in regenerative medicine, exerting pleiotropic functions by producing soluble factors, such as exosomes. MSCs and their exosomes (MSCs‐Exo) kinetic are affected by ageing and other aged exosomes. Exosomes biogenesis from aged MSCs is accelerated and their exosomal cargoes, such as miRNAs, vary as compared to those of normal cells. Besides, exosomes from aged MSCs loss their regenerative potential and may negatively influence the function of recipient cells. MSCs‐Exo can improve ageing and age‐related diseases; however, the detailed mechanisms remain yet elusive. Although exosomes‐therapy may serve as a new approach to combat ageing, the translation of preclinical results to clinic needs more extensive investigation on exosomes both on their biology and related techniques. Overall, scrutiny on the effect of ageing on MSCs and vice versa is vital for designing novel therapy using MSCs with focus on the management of older individuals.     

Emerging Piezo1 signaling in inflammation and atherosclerosis; a potential therapeutic target

Purpose of Review: Atherosclerosis is the principal cause of cardiovascular diseases (CVDs) which are the major cause of death worldwide. Mechanical force plays an essential role in cardiovascular health and disease. To bring the awareness of mechanosensitive Piezo1 role in atherosclerosis and its therapeutic potentials we review recent literature to highlight its involvement in various mechanisms of the disease.Recent Findings: Recent studies reported Piezo1 channel as a sensor, and transducer of various mechanical forces into biochemical signals, which affect various cellular activities such as proliferation, migration, apoptosis and vascular remodeling including immune/inflammatory mechanisms fundamental phenomenon in atherogenesis.Summary: Numerous evidences suggest Piezo1 as a player in different mechanisms of cell biology, including immune/inflammatory and other cellular mechanisms correlated with atherosclerosis. This review discusses mechanistic insight about this matter and highlights the drugability and therapeutic potentials consistent with emerging functions Piezo1 in various mechanisms of atherosclerosis. Based on the recent works, we suggest Piezo1 as potential therapeutic target and a valid candidate for future research. Therefore, a deeper exploration of Piezo1 biology and translation towards the clinic will be a novel strategy for treating atherosclerosis and other CVDs.     

Circulating exosomal miRNAs in cardiovascular disease pathogenesis: New emerging hopes

Cardiovascular diseases (CVDs) are one of the leading causes of morbidity and mortality. Standard therapies have failed to significantly increase patients’ survival. Moreover, the majority of conventional screening procedures are ineffective for the diagnosis of CVDs at early stages. Accumulating evidence suggests that numerous cell types release a class of nano-sized vesicles named exosomes into the extracellular space. Exosomes are widely distributed in various body fluids and contain a number of diverse biomolecules such as proteins, lipids, and both mRNA and noncoding RNAs which reflect host-cell molecular architecture. MicroRNAs (miRNAs), which can be found in exosomes, could be taken up by both neighboring and distal cells. Not only has recent evidence indicated the regulatory role of exosomal miRNAs in the pathogenesis of CVD, but it has also been shown that differential expression of exosomal miRNAs in CVDs has made them promising biomarkers for early detection of CVDs. Owing to these remarkable features, exosomal miRNAs have emerged as hot spots in research. This review summarizes the role of exosomal miRNAs in the pathogenesis of CVDs and discusses their potential application in the clinical setting as both therapeutic and diagnostic tools.     

Exosomes: A New Weapon to Treat the Central Nervous System

The potential of exosomes to treat central nervous system (CNS) pathologies has been recently demonstrated. These studies make way for a complete new field that aims to exploit the natural characteristics of these vesicles, considered for a long time as side products of physiological cellular pathways. Recently, however, the biological significance of exosomes has been evaluated and exosomes can now be viewed upon as new relevant functional entities for development of novel therapeutic strategies. In this review, we aim to summarize the state-of-the-art role of exosomes in the CNS and to speculate about possible future therapeutic applications of exosomes. In particular, we will speculate about the use of these vesicles as a substitute of cell-based therapies for the treatment of brain damage and review the potential of exosomes as drug delivery vehicles for the CNS.     

Insulin‐like growth factors and their potential role in cardiac epigenetics

Cardiovascular disease (CVD) constitutes a major public health threat worldwide, accounting for 17.3 million deaths annually. Heart disease and stroke account for the majority of healthcare costs in the developed world. While much has been accomplished in understanding the pathophysiology, molecular biology and genetics underlying the diagnosis and treatment of CVD, we know less about the role of epigenetics and their molecular determinants. The impact of environmental changes and epigenetics in CVD is now emerging as critically important in understanding the origin of disease and the development of new therapeutic approaches to prevention and treatment. This review focuses on the emerging role of epigenetics mediated by insulin like‐growth factors‐I and ‐II in major CVDs such as heart failure, cardiac hypertrophy and diabetes.     

Physical exosome:exosome interactions

Exosomes are extracellular nanovesicles that mediate a number of cellular processes, including intracellular signalling. There are many published examples of exosome–exosome dimers; however, their relevance has not been explored. Here, we propose that cells release exosomes to physically interact with incoming exosomes, forming dimers that we hypothesize attenuate incoming exosome‐mediated signalling. We discuss experiments to test this hypothesis and potential relevance in health and disease.     

Therapeutic potential of A2 adenosine receptor pharmacological regulators in the treatment of cardiovascular diseases,recent progress,and prospective

Adenosine and its analogs are of particular interest as potential therapeutic agents for treatment of cardiovascular diseases (CVDs). A2 adenosine receptor subtypes (A2a and A2b) are extensively expressed in cardiovascular system, and modulation of these receptors using A2 adenosine receptor agonists or antagonists regulates heart rate, blood pressure, heart rate variability, and cardiovascular toxicity during both normoxia and hypoxia conditions. Regulation of A2 adenosine receptor signaling via specific and novel pharmacological regulators is a potentially novel therapeutic approach for a better understanding and hence a better management of CVDs. This review summarizes the role of pharmacological A2 adenosine receptor regulators in the pathogenesis of CVDs.     

Exosomes as a novel cell-free therapeutic approach in gastrointestinal diseases

Cell communication through extracellular vesicles (EVs) has been defined for many years and it is not limited only to neighboring cells, but also distant ones in organisms receive these signals. These vesicles are secreted from the variety of cells and are composed of a distinctive component such as proteins, lipids, and nucleic acids. EVs have different classified subgroups regarding their cell origin, in this context, exosomes are the most appealing particles in cell biology, especially clinical in recent years and are represented as novel therapeutic agents with numerous advantages alongside and/or over cell therapy. However, cell therapy had a hopeful outcome in gastrointestinal diseases which have minimal alternatives in their treatments. Inflammatory bowel disease (IBD), liver fibrosis, gastrointestinal cancers are the examples that cell therapy and immunotherapy were applied in their treatment, therefore, the cell products like exosomes are the beneficial option in their treatment even cancers with promising results in animal models. In this review, we consider the main defined biogenesis, function, and component of secreted exosomes in different cells with a specific focus on the potential application of these exosomes as a cell-free therapeutic approach in gastrointestinal diseases like IBD, gastric cancer, and colon cancer. Additionally, exosomes role as therapeutic reagents mainly mesenchymal stem cells and dendritic cell-derived exosomes in different studies have been under intense investigation and even they are being studied in different clinical trials. Therefore, all these striking functions described for secretome implies the importance of these biocarriers.     

Application of mesenchymal stem cell exosomes and their drug‐loading systems in acute liver failure

Stem cell exosomes are nanoscale membrane vesicles released from stem cells of various origins that can regulate signal transduction pathways between liver cells, and their functions in intercellular communication have been recognized. Due to their natural substance transport properties and excellent biocompatibility, exosomes can also be used as drug carriers to release a variety of substances, which has great prospects in the treatment of critical and incurable diseases. Different types of stem cell exosomes have been used to study liver diseases. Due to current difficulties in the treatment of acute liver failure (ALF), this review will outline the potential of stem cell exosomes for ALF treatment. Specifically, we reviewed the pathogenesis of acute liver failure and the latest progress in the use of stem cell exosomes in the treatment of ALF, including the role of exosomes in inhibiting the ALF inflammatory response and regulating signal transduction pathways, the advantages of stem cell exosomes and their use as a drug‐loading system, and their pre‐clinical application in the treatment of ALF. Finally, the clinical research status of stem cell therapy for ALF and the current challenges of exosome clinical transformation are summarized.     

Exosomes in carcinogenesis: molecular palkis carry signals for the regulation of cancer progression and metastasis

Exosomes, which act as biological cargo vessels, are cell-released, phospholipid-enclosed vesicles. In eukaryotic cells, exosomes carry and exchange biological materials or signals for the benefit or detriment to the cells. Thereby, we consider exosomes to be molecular Palkis (carriers). Although exosomes are currently one of the most popularly researched cellular entities, they have remained largely enigmatic and warrant continued investigation into their structure and functions. These membraned vesicles are between 30 and 150 nm in diameter and are actively secreted by all cell types. While initially considered cellular “trash bags,” recent years have revealed exosomes to be dynamic and multi-functional vesicles that may play a crucial role in cancer development, progression and metastasis. Thereby, they have the potential to be used in development of therapeutic modalities for cancer and other diseases. As more research studies emerge, it’s becoming evident that exosomes are released by cells with a purpose and are representatives of certain cell types and disease conditions. Hence, they may also be used as biomarkers for the detection of cancer initiation, progression and organotropic metastatic growth of cancer cells. This review will focus on the recent developments achieved in identifying the role of exosomes in cancer development and progression as well as therapeutic implications. The review will also discuss the pitfalls of methodologies used for the extraction of exosomes.     

Circular RNA in cardiovascular disease: Expression,mechanisms and clinical prospects

Circular RNAs (circRNAs) are a group of covalently closed, endogenous, non-coding RNAs, which exist widely in human tissues including the heart. Increasing evidence has shown that cardiac circRNAs play crucial regulatory roles in cardiovascular diseases (CVDs). In this review, we aimed to provide a systemic understanding of circRNAs with a special emphasis on the cardiovascular system. We have summarized the current research on the classification, biogenesis and properties of circRNAs as well as their participation in the pathogenesis of CVDs. CircRNAs are conserved, stable and have specific spatiotemporal expression; thus, they have been accepted as a potential diagnostic marker or an incremental prognostic biomarker for CVDs.     

Discovery of New D-Ring Modified Isosteviol Derivatives as Potent Cardioprotective Agents against Oxidative Stress-Trigged Damage

Cardiovascular diseases (CVDs) are a major global health concern, and oxidative stress is known to play a central role in their pathogenesis. The identification of new agents capable of inhibiting oxidative stress presents a promising strategy for preventing and treating CVDs. Natural products and their derivatives offer a valuable source for drug discovery, and isosteviol, a readily available natural product, is known to exhibit cardioprotective effects. In this study, 22 new D-ring modified isosteviol derivatives were synthesized and evaluated for their cardioprotective effect in vivo using the zebrafish cardiomyopathy model. The findings revealed that derivative 4e exhibited the most potent cardioprotective effect, surpassing its parent compound isosteviol and the positive drug levosimendan. At 1 μM, derivative 4e significantly protected the cardiomyocytes from injury, while at 10 μM it effectively maintained normal heart phenotypes, preventing cardiac dysfunction in zebrafish. Further investigation demonstrated that 4e protected cardiomyocytes from oxidative stress-induced damage by inhibiting reactive oxygen species overaccumulation, activating superoxide dismutase 2 expression, and enhancing the endogenous antioxidant defense system. These results suggest that isosteviol derivatives, particularly 4e , have the potential to serve as a novel class of cardioprotective agents for the prevention and treatment of CVDs.     

Exosomes are the novel players involved in the beneficial effects of exercise on type 2 diabetes

Exosomes contain regulatory signals such as lipids, proteins, and nucleic acids which can be transferred to adjacent or remote cells to mediate cell-to-cell communication. Exercise is a positive lifestyle for metabolic health and a nonpharmacological treatment of insulin resistance and metabolic diseases. Moreover, exercise is a stressor that induces cellular responses including gene expression and exosome release in various types of cells. Exosomes can carry the characters of parent cells by their modified cargoes, representing novel mechanisms for the effects of exercise. Here, we present a review of exosomes as the perspective players in mediating exercise's beneficial impacts on type 2 diabetes (T2D).     

Stem cell-derived exosomes-an emerging tool for myocardial regeneration

Cardiovascular diseases(CVDs) continue to represent the number one cause of death and disability in industrialized countries. The most severe form of CVD is acute myocardial infarction(AMI), a devastating disease associated with high mortality and disability. In a substantial proportion of patients who survive AMI, loss of functional cardiomyocytes as a result of ischaemic injury leads to ventricular failure, resulting in significant alteration to quality of life and increased mortality. Therefore, many attempts have been made in recent years to identify new tools for the regeneration of functional cardiomyocytes. Regenerative therapy currently represents the ultimate goal for restoring the function of damaged myocardium by stimulating the regeneration of the infarcted tissue or by providing cellsthat can generate new myocardial tissue to replace the damaged tissue. Stem cells(SCs) have been proposed as a viable therapy option in these cases. However, despite the great enthusiasm at the beginning of the SC era, justified by promising initial results, this therapy has failed to demonstrate a significant benefit in large clinical trials. One interesting finding of SC studies is that exosomes released by mesenchymal SCs(MSCs) are able to enhance the viability of cardiomyocytes after ischaemia/reperfusion injury, suggesting that the beneficial effects of MSCs in the recovery of functional myocardium could be related to their capacity to secrete exosomes. Ten years ago, it was discovered that exosomes have the unique property of transferring miRNA between cells, acting as miRNA nanocarriers. Therefore, exosomebased therapy has recently been proposed as an emerging tool for cardiac regeneration as an alternative to SC therapy in the post-infarction period. This review aims to discuss the emerging role of exosomes in developing innovative therapies for cardiac regeneration as well as their potential role as candidate biomarkers or for developing new diagnostic tools.     

Role of cardiac progenitor cell‐derived exosome‐mediated microRNA‐210 in cardiovascular disease

Cardiac progenitor cells are considered to be one of the most promising stem cells for heart regeneration and repair. The cardiac protective effect of CPCs is mainly achieved by reducing tissue damage and/or promoting tissue repair through a paracrine mechanism. Exosome is a factor that plays a major role in the paracrine effect of CPCs. By delivering microRNAs to target cells and regulating their functions, exosomes have shown significant beneficial effects in slowing down cardiac injury and promoting cardiac repair. Among them, miRNA‐210 is an important anoxic‐related miRNA derived from CPCs exosomes, which has great cardiac protective effect of inhibiting myocardial cell apoptosis, promoting angiogenesis and improving cardiac function. In addition, circulating miR‐210 may be a useful biomarker for the prediction or diagnosis of related cardiovascular diseases. In this review, we briefly reviewed the mechanism of miR‐210 derived from CPCs exosomes in cardiac protection in recent years.     

外泌体在免疫调控及肿瘤发生中的功能

已知细胞间的信息交流不仅可以通过直接接触,或释放信号分子等方式,同时还存在另一种细胞通讯方式即释放外泌体。外泌体是由细胞分泌,直径为30～100 nm的囊泡结构。外泌体含有蛋白质、脂质、mRNAs和miRNAs等成分,并且能够靶向运输到其他细胞或组织中,从而在细胞间的信息交流、物质传递方面发挥重要作用。本文对外泌体的基本特征、形成过程、功能以及在疾病诊断与治疗中的应用等方面进行简要综述,重点介绍外泌体在免疫调控和肿瘤发生方面的功能。外泌体作为一种广泛存在的亚细胞成分,虽然体积小,组成成分简单,然而,其复杂功能具有重要的研究价值。对外泌体功能的深入了解将为肿瘤等疾病的预防和治疗提供更多的诊断标志物、疫苗以及治疗思路与手段。     

Role of interleukin‐15 in cardiovascular diseases

Interleukin (IL)‐15 is a recently identified cytokine, which belongs to the interleukin‐2(IL‐2) family, and plays an important role in innate and adaptive immunoreaction. Given the fact that the structure of IL‐15 is partially similar to IL‐2, they share some common biological effects, including immunoregulation. IL‐2 was proven to protect cardiac function in mouse myocardial infarction models. Cardiovascular diseases (CVDs) dominate the cause of mortality worldwide. Besides atherosclerosis, inflammation is also widely involved in the pathogenesis of many CVDs including hypertension, heart failure (HF) and aneurysm. IL‐15, as a pro‐inflammatory cytokine, is up‐regulated in some cardiovascular diseases, such as myocardial infarction and atherosclerosis. The current understanding of IL‐15, including its signal pathway and cellular function, was described. Furthermore, IL‐15 has a protective effect in myocardial infarction and myocarditis by decreasing cardiomyocyte death and improving heart function. The inhibited effect of IL‐15 in ductus arteriosus (DA) should be focused on. IL‐15 promoted atherogenesis. IL‐15 may be a good target in treatment of cardiovascular diabetology. Finally, future research direction of IL‐15 deserves attention. Since IL‐15 plays several roles in CVDs, understanding the role of the IL‐15/IL‐15R system may provide a scientific basis for the development of new approaches that use IL‐15 for the treatment of CVDs.