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For therapeutic materials to be successfully delivered to the heart, several barriers need to be overcome, including the anatomical challenges of access, the mechanical force of the blood flow, the endothelial barrier, the cellular barrier and the immune response. Various vectors and delivery methods have been proposed to improve the cardiac-specific uptake of materials to modify gene expression. Viral and non-viral vectors are widely used to deliver genetic materials, but each has its respective advantages and shortcomings. Adeno-associated viruses have emerged as one of the best tools for heart-targeted gene delivery. In addition, extracellular vesicles, including exosomes, which are secreted by most cell types, have gained popularity for drug delivery to several organs, including the heart. Accumulating evidence suggests that extracellular vesicles can carry and transfer functional proteins and genetic materials into target cells and might be an attractive option for heart-targeted delivery. Extracellular vesicles or artificial carriers of non-viral and viral vectors can be bioengineered with immune-evasive and cardiotropic properties. In this Review, we discuss the latest strategies for targeting and delivering therapeutic materials to the heart and how the knowledge of different vectors and delivery methods could successfully translate cardiac gene therapy into the clinical setting.For therapeutic materials to be delivered to the heart, several barriers need to be overcome. In this Review, Ishikawa and colleagues discuss strategies for targeted delivery of therapeutic materials to the heart, including the use of adeno-associated viruses and exosomes, with a focus on agents directed at modifying gene expression.

Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have certain properties that allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be bioengineered to increase their stability, bioactivity, presentation to acceptor cells and capacity for on-target binding at both cell-type-specific and tissue-specific levels. Bioengineering of EVs involves the modification of the donor cell before EV isolation or direct modification of the EV properties after isolation. The therapeutic potential of native EVs and bioengineered EVs has been only minimally explored in the context of cardiovascular diseases. Efforts to harness the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of research into molecular-compound delivery. In this Review, we outline the endogenous properties of EVs that make them natural delivery agents as well as the features that can be improved by bioengineering. We also discuss the therapeutic applications of native and bioengineered EVs to cardiovascular diseases and examine the opportunities and challenges that need to be addressed to advance this research area, with an emphasis on clinical translation.Extracellular vesicles are a heterogeneous group of natural particles that can deliver their biologically active molecular cargo to recipient cells. In this Review, the authors outline the endogenous properties of extracellular vesicles that make them natural delivery agents and the features that can be improved by bioengineering for the treatment of cardiovascular diseases.

Extracellular vesicles (EVs) represent an important mode of intercellular communication. Research in this field has grown rapidly in the last few years, and there is a plethora of techniques for the isolation and characterization of EVs, many of which are poorly standardized. EVs are heterogeneous in size, origin and molecular constituents, with considerable overlap in size and phenotype between different populations of EVs. Little is known about current practices for the isolation, purification and characterization of EVs. We report here the first large, detailed survey of current worldwide practices for the isolation and characterization of EVs. Conditioned cell culture media was the most widely used material (83%). Ultracentrifugation remains the most commonly used isolation method (81%) with 59% of respondents use a combination of methods. Only 9% of respondents used only 1 characterization method, with others using 2 or more methods. Sample volume, sample type and downstream application all influenced the isolation and characterization techniques employed.

Secreted membrane-enclosed vesicles, collectively called extracellular vesicles (EVs), which include exosomes, ectosomes, microvesicles, microparticles, apoptotic bodies and other EV subsets, encompass a very rapidly growing scientific field in biology and medicine. Importantly, it is currently technically challenging to obtain a totally pure EV fraction free from non-vesicular components for functional studies, and therefore there is a need to establish guidelines for analyses of these vesicles and reporting of scientific studies on EV biology. Here, the International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs.

Cardiovascular disease remains the leading cause of morbidity and mortality in the world. Thus, therapeutic interventions to circumvent this growing burden are of utmost importance. Extracellular vesicles (EVs) actively secreted by most living cells, play a key role in paracrine and endocrine intercellular communication via exchange of biological molecules. As the content of secreted EVs reflect the physiology and pathology of the cell of their origin, EVs play a significant role in cellular homeostasis, disease pathogenesis and diagnostics. Moreover, EVs are gaining popularity in clinics as therapeutic and drug delivery vehicles, transferring bioactive molecules such as proteins, genes, miRNAs and other therapeutic agents to target cells to treat diseases and deter disease progression. Despite our limited but growing knowledge of EV biology, it is imperative to understand the complex mechanisms of EV cargo sorting in pursuit of designing next generation EV-based therapeutic delivery systems. In this review, we highlight the mechanisms of EV cargo sorting and methods of EV bioengineering and discuss engineered EVs as a potential therapeutic delivery system to treat cardiovascular disease.

Extracellular vesicles (EVs) are heterogeneous entities secreted by cells into their microenvironment and systemic circulation. Circulating EVs carry functional small RNAs and other molecular footprints from their cell of origin, and thus have evident applications in liquid biopsy, therapeutics, and intercellular communication. Yet, the complete transcriptomic landscape of EVs is poorly characterized due to critical limitations including variable protocols used for EV‐RNA extraction, quality control, cDNA library preparation, sequencing technologies, and bioinformatic analyses. Consequently, there is a gap in knowledge and the need for a standardized approach in delineating EV‐RNAs. Here, we address these gaps by describing the following points by (1) focusing on the large canopy of the EVs and particles (EVPs), which includes, but not limited to – exosomes and other large and small EVs, lipoproteins, exomeres/supermeres, mitochondrial‐derived vesicles, RNA binding proteins, and cell‐free DNA/RNA/proteins; (2) examining the potential functional roles and biogenesis of EVPs; (3) discussing various transcriptomic methods and technologies used in uncovering the cargoes of EVPs; (4) presenting a comprehensive list of RNA subtypes reported in EVPs; (5) describing different EV‐RNA databases and resources specific to EV‐RNA species; (6) reviewing established bioinformatics pipelines and novel strategies for reproducible EV transcriptomics analyses; (7) emphasizing the significant need for a gold standard approach in identifying EV‐RNAs across studies; (8) and finally, we highlight current challenges, discuss possible solutions, and present recommendations for robust and reproducible analyses of EVP‐associated small RNAs. Overall, we seek to provide clarity on the transcriptomics landscape, sequencing technologies, and bioinformatic analyses of EVP‐RNAs. Detailed portrayal of the current state of EVP transcriptomics will lead to a better understanding of how the RNA cargo of EVPs can be used in modern and targeted diagnostics and therapeutics. For the inclusion of different particles discussed in this article, we use the terms large/small EVs, non‐vesicular extracellular particles (NVEPs), EPs and EVPs as defined in MISEV guidelines by the International Society of Extracellular Vesicles (ISEV). Overview of the RNA landscape of EVPs. Most commonly studied small EVP subtypes ranging from a diameter of ~1 nm to > 200 nm (top), and the most common types of RNA found within EVPs ranging from miRNA, piRNA, tRNA, snRNA, YRNA, circRNA, snoRNA, lncRNAs, mRNA, and rRNA (bottom).

The Western diet (WD) has been linked to various structural and functional alterations in the left ventricle (LV), but the molecular response of the right ventricle (RV) remains largely unknown. Given the RV’s distinct anatomical and functional characteristics, it is crucial to understand how long-term WD exposure affects RV gene expression, especially in a sex-specific context. Our objective was to perform gene expression profiling of the RV late responses to WD in wild-type mice. Male and female C57BL/6J mice were fed a WD for 125 days from 300 to 425 days of age, and RV tissues were collected at 530 and 640/750 (female/male) days. mRNA sequencing was performed on RV tissues to identify differentially expressed genes (DEGs) between WD-fed and normal diet (ND)-fed groups. Data processing and analysis were conducted using the STAR aligner and DESeq2. WD-induced RV transcriptomic changes were characterized by differential expression of genes associated with cardiac remodeling and transcriptional regulation in both sexes. In females, additional genes showing altered expression were associated with immune response, whereas in males, changes were more limited, primarily involving genes related to circadian rhythm and cardiac remodeling. Echocardiography revealed modest, sex-specific differences: WD-fed females showed a decrease in right-ventricular internal diameter in diastole and a trend toward increased pulmonary trunk diameter, whereas males showed no notable changes. These exploratory results suggest that WD is associated with modest transcriptomic changes in the RV in both sexes, with only minor structural differences observed in females, indicating subtle sex-specific effects after a switch to normal chow.

Space irradiation (IR) is an important health risk for deep-space missions. We reported heart failure with preserved ejection fraction like cardiac phenotype 660-days following exposure to a single-dose of a simplified galactic cosmic ray simulation (simGCRsim) only in males with functional and structural impairment in left ventricular (LV) function. This sex-based dichotomy prompted us to investigate sex-specific changes in the LV transcriptome in three-month-old male and female mice exposed to 137 Cs-γ- or simGCRsim-IR. Non-IR male and female (10 each) mice served as controls. LVs were collected at 440/660- and 440/550-days post-IR, male and female, respectively. RNA sequencing, differential gene expression, and functional annotation were performed on tissues from 5 mice/group. Sex and post-IR time points had the greatest influence on gene expression, surpassing the IR-type effects. SimGCRsim-IR showed more persistent transcriptome changes than γ-IR. We suggest that the single IR effects can persist up to 550–660 days, with overwhelmingly sex-biased responses at individual gene expression level.

While it is well known that 98–99% of the human genome does not encode proteins, but are nevertheless transcriptionally active and give rise to a broad spectrum of noncoding RNAs [ncRNAs] with complex regulatory and structural functions, specific functions have so far been assigned to only a tiny fraction of all known transcripts. On the other hand, the striking observation of an overwhelmingly growing fraction of ncRNAs, in contrast to an only modest increase in the number of protein-coding genes, during evolution from simple organisms to humans, strongly suggests critical but so far essentially unexplored roles of the noncoding genome for human health and disease pathogenesis. Research into the vast realm of the noncoding genome during the past decades thus lead to a profoundly enhanced appreciation of the multi-level complexity of the human genome. Here, we address a few of the many huge remaining knowledge gaps and consider some newly emerging questions and concepts of research. We attempt to provide an up-to-date assessment of recent insights obtained by molecular and cell biological methods, and by the application of systems biology approaches. Specifically, we discuss current data regarding two topics of high current interest: (1) By which mechanisms could evolutionary recent ncRNAs with critical regulatory functions in a broad spectrum of cell types (neural, immune, cardiovascular) constitute novel therapeutic targets in human diseases? (2) Since noncoding genome evolution is causally linked to brain evolution, and given the profound interactions between brain and immune system, could human-specific brain-expressed ncRNAs play a direct or indirect (immune-mediated) role in human diseases? Synergistic with remarkable recent progress regarding delivery, efficacy, and safety of nucleic acid-based therapies, the ongoing large-scale exploration of the noncoding genome for human-specific therapeutic targets is encouraging to proceed with the development and clinical evaluation of novel therapeutic pathways suggested by these research fields.

[...]most survey participants are in favour of standards, with a majority of respondents supporting MISEV2014. Only minimal overlap between the \"volunteers\" and \"volunteered\" was observed. [...]in total, approximately 85 unique individuals were identified as possible contributors. Functional studies should include: a) Dose-response studies b) Process controls to rule out influence of serum components/ other possible contaminants c-i.) Density gradients to show activity is intrinsic to EVs, not just associated or c-ii.) EV depletion to remove activity or c-iii.) EV/cell labelling (e.g., fluorescent labelling, with careful interpretation) Text Box 2. Available form: https://www.ncbi.nlm.nih.gov/pubmed/26799652 Kenneth W. Witwer Departments of Molecular and Comparative Pathobiology and Neurology, The Johns Hopkins University School of Medicine, Baltimore, USA © kwitwer1@jhmi.edu ©http://orcid.org/0000-0003-1664-4233 Carolina Soekmadji Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia ©http://orcid.org/0000-0002-6920-6627 Andrew F. Hill Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia ©http://orcid.org/0000-0001-5581-2354 Marca H. Wauben Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Edit I. Buzás Department of Genetics, Cell- and Immunobiology, Semmelweis University and MTA-SE Immunoproteogenomics Extracellular Vesicle Research Group, Budapest, Hungary Dolores Di Vizio Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences, and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA Juan M. Falcon-Perez Exosomes Laboratory & Metabolomics Platform, CIC bioGUNE, CIBERehd, Derio, Spain IKERBASQUE Research Science Foundation, Bilbao, Spain Chris Gardiner Research Department of Haematology, University College London, London, UK Fred Hochberg Neurosurgery, University of California at San Diego, San Diego, CA, USA The Scintillon Institute, La Jolla, CA, USA Igor V. Kurochkin Central Research Laboratories, Sysmex Co, Kobe, Japan Jan Lötvall Codiak BioSciences, Cambridge, MA, USA Krefting Research Centre, University of Gothenburg, Gothenburg, Sweden ©http://orcid.org/0000-0001-9195-9249 Suresh Mathivanan Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia Rienk Nieuwland Department of Clinical Chemistry and Vesicle Observation Centre, Academic Medical Centre of the University of Amsterdam, Amsterdam, The Netherlands Susmita Sahoo Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Hidetoshi Tahara Department of Cellular and Molecular Biology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan Ana Claudia Torrecilhas Departamento de Ciencias Farmacéuticas, UNIFESP, Diadema, Brazil Alissa M. Weaver Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA ©http://orcid.org/0000-0002-4096-8636 Hang Yin Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, China Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA Lei Zheng Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China Yong Song Gho Department of Life Sciences, POSTECH (Pohang University of Science and Technology), Pohang, South Korea Peter Quesenberry Brown Medical School, Rhode Island Hospital, Providence, RI, USA Clotilde Théry Institut Curie, INSERM U932, PSL Research University, Paris, France © clotilde.thery@curie.fr Received 29 September 2017; accepted 20 October 2017