MicroRNA-126 (miR-126) has emerged as one of the most extensively studied microRNAs in the context of human diseases, particularly in vascular disorders and cancer. Its high degree of conservation across vertebrates underscores its evolutionary significance and essential functional roles. Extensive research has been devoted to elucidating the molecular mechanisms through which miR-126 modulates key physiological and pathological processes, including angiogenesis, immune response, inflammation, tumor growth, and metastasis. Furthermore, miR-126 plays a causal role in the pathogenesis of various diseases, serving as potential biomarkers for disease prediction, diagnosis, prognosis and drug response, as well as a promising therapeutic target. In this review, we synthesize findings from 283 articles, focusing on the roles of miR-126 in critical biological processes such as cell development, survival, cycle regulation, proliferation, migration, invasion, communication, and metabolism. Additionally, miR-126 represents a promising candidate for miRNA-based therapeutic strategies. A comprehensive understanding and evaluation of miR-126 are crucial for advancing its clinical applications and therapeutic potential.

MicroRNAs (miRNAs), a class of endogenous small RNAs with lengths of approximately 19-24 nucleotides, play important regulatory roles in cells. In recent years, miR-363 has emerged as a prominent member of the miR-92a family, participating in various biological functions, including cellular proliferation, cycle, migration, and apoptosis. In particular, miR-363 plays a critical role in acute kidney injury, renal fibrosis, and diabetic nephropathy and can serve as a biomarker for the diagnosis of renal cell carcinoma. Ongoing research is exploring its potential as a biomarker of other kidney diseases. This review focuses on the role of miR-363 in kidney diseases, elucidating its regulatory mechanisms and exploring its possible value as a biomarker of kidney diseases.

Acute kidney injury (AKI) is a common health problem that leads to high morbidity and potential mortality. The failure of conventional treatments to improve forms of this condition highlights the need for innovative and effective treatment approaches. Regenerative therapies with Renal Progenitor Cells (RPCs) have been proposed as a promising new strategy. A growing body of evidence suggests that progenitor cells differentiated from different sources, including human embryonic stem cells (hESCs), can effectively treat AKI.

Here, we describe a method for generating RPCs and directed human Embryoid Bodies (EBs) towards CD133+CD24+ renal progenitor cells and evaluate their functional activity in alleviating AKI.

The obtained results show that hESCs-derived CD133+CD24+ RPCs can engraft into damaged renal tubules and restore renal function and structure in mice with gentamicin-induced kidney injury, and significantly decrease blood urea nitrogen levels, suppress oxidative stress and inflammation, and attenuate histopathological disturbances, including tubular necrosis, tubular dilation, urinary casts, and interstitial fibrosis.

The results suggest that RPCs have a promising regenerative potential in improving renal disease and can lay the foundation for future cell therapy and disease modeling.

Extracellular vesicles (EVs) are membrane bound vesicles secreted from cells into the extracellular space which have an emerging role in both normal kidney physiology and the pathophysiology of kidney injury, predominantly as mediators of intercellular communication. EVs contain proteins and RNA cargo which reflect their cell of origin and can be isolated from the urine of cats and dogs. The majority of urinary EVs (uEVs) originate from the kidney, and both the uEV proteome and transcriptome have been investigated as sources of biomarkers of kidney disease. In addition to their possible diagnostic role, EVs may also have therapeutic potential, and veterinary species have been used as models to demonstrate the efficacy of exogenous EVs derived from mesenchymal stromal cells in the treatment of acute kidney injury. Furthermore, bioengineered EVs may represent a novel vehicle for the administration of drugs or therapeutic nucleic acids in kidney disease. This article reviews the biological functions of EVs within the kidney, techniques for their isolation, and their potential use as biomarkers and therapeutic agents, with particular focus on the potential significance to veterinary patients.

Exosomes are vesicles produced by the human body for carrying certain information from one cell to another. The carriers are nanosized vesicles carrying a wide variety of cargo like RNA, DNA, and proteins. Exosomes are also being used in the early diagnosis of various diseases and disorders. Current research focuses on exosomes tailoring for achieving therapeutic potential in various diseases and disorders. Besides this, their biocompatibility, stability, adjustable efficacy, and targeting properties make them attractive vehicles for formulation developers. Various preclinical studies suggested that the exosome culture cells are also modified with certain genes to achieve the desirable properties of resultant exosomes. The human body also produces some other vesicles like Ectosomes and Exomeres produced along with exosomes. Additionally, vesicles like Migrasomes are produced by migrating cells and apoptotic bodies, and Oncosomes are produced by cancer cells which can also be useful for the diagnosis of various diseases and disorders. For the separation of desired exosomes from other vesicles some latest techniques that can be useful viz differential centrifugation, density gradient centrifugation, and immunoaffinity purification have been discussed. Briefly, this review summarized various techniques of isolation of purified exosomes along with an overview of the application of exosomes in various neurodegenerative disorders and cancer along with various latest aspects of exosomes in disease progression and management which might be beneficial for the researchers.

Early diagnosis of acute kidney injury (AKI) is limited with current tools. MicroRNAs (miRNAs) are implicated in AKI pathogenesis in preclinical models, but less is known about their role in humans. We conducted a systematic review to identify dysregulated miRNAs in humans with AKI.

We searched Ovid MEDLINE, Embase, Web of Science, and CENTRAL (August 21, 2023) for studies of human subjects with AKI. We excluded reviews and pre-clinical studies without human data. The primary outcome was dysregulated miRNAs in AKI. Two reviewers screened abstracts, reviewed full texts, performed data extraction and quality assessment (Newcastle Ottawa Scale).

We screened 2,456 reports and included 92 for synthesis without meta-analysis. All studies except one were observational. Studies were grouped by etiology of AKI: cardiac surgery-associated (CS-AKI, n = 13 studies), sepsis (n = 25), nephrotoxic (n = 9), kidney transplant (n = 26), and other causes (n = 19). In total, 128 miRNAs were identified to be dysregulated across AKI studies (45 miRNAs upregulated, 55 downregulated, 28 both). miR-21 was the most frequently reported (n = 17 studies) and it was increased in all etiologies except CS-AKI where it was decreased (n = 3 studies). Study limitations included bias due to targeted approaches, absence of clinical data/controls, and miRNA normalization methods. Overall study quality was fair (median 5/9, range 2-8 points).

Dysregulated miRNAs, particularly miR-21, have potential as AKI biomarkers. These results should be interpreted cautiously due to methodological limitations. Standardized methods and unbiased approaches are needed to validate candidate miRNA biomarkers.Registration: International Prospective Register of Systematic Reviews (PROSPERO CRD42020201253).

Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-EVs) are valuable in nanomedicine as natural nanocarriers, carrying information molecules from their parent cells and fusing with targeted cells. miRNA-126, specific to endothelial cells and derived from these vesicles, supports vascular integrity and angiogenesis and has protective effects in kidney diseases.

This study investigates the delivery of miRNA-126 and anti-miRNA-126 via UC-EVs as natural nanocarriers for treating nephrotoxic injury in vitro.

The umbilical cord-derived mesenchymal stem cell and UC-EVs were characterized according to specific guidelines. Rat kidney proximal tubular epithelial cells (tubular cells) were exposed to nephrotoxic injury through of gentamicin and simultaneously treated with UC-EVs carrying miRNA-126 or anti-miRNA-126. Specific molecules that manage cell cycle progression, proliferation cell assays, and newly synthesized DNA and DNA damage markers were evaluated.

We observed significant increases in the expression of cell cycle markers, including PCNA, p53, and p21, indicating a positive cell cycle regulation with newly synthesized DNA via BrDU. The treatments reduced the expression of DNA damage marker, such as H2Ax, suggesting a lower rate of cellular damage.

The UC-EVs, acting as natural nanocarriers of miRNA-126 and anti-miRNA-126, offer nephroprotective effects in vitro. Additionally, other components in UC-EVs, such as proteins, lipids, and various RNAs, might also contribute to these effects.

Extracellular vesicle (EV) secretion and cargo composition are dysregulated in metabolic diseases. This study aimed to identify changes in the EV size profile and protein cargoes in diet-induced obesity following time-restricted feeding (TRF) and to establish the role of EVs in obesity-related metabolic responses.

Mice were fed a high-fat diet (HFD) for 18 weeks prior to being placed either ad libitum or a time-restricted feeding for an additional 10 weeks. Mice on a normal chow ad libitum served as the control. The TRF group had food available for 10 hours and fasted for 14 hours per day.

The serum EV size profile and amount displayed sex- and age-dependent changes in HFD-induced obesity, with age reducing EV amounts. HFD decreased small EV populations and increased larger EV populations, while TRF reversed these changes. Quantitative proteomic analysis showed that the abundance and composition of EV proteins changed in response to both acute stimulation with lipopolysaccharides (LPS) and HFD. Gene ontology analysis identified specific sets of EV proteins and their involved biological processes, reflecting the effect of LPS and HFD, as well as the reversal effect of TRF on metabolic and inflammatory pathways. EV proteins altered by HFD and those reversed by TRF had low protein overlap but significant functional overlap in biological processes. TRF activated the PPAR signaling pathway and the AKT-mTOR signaling pathway. The most significant impacts of HFD and TRF were observed on lipoprotein and carbohydrate metabolism, complement system, and neutrophil degranulation. The reversal effect of TRF on the complement system was pathway-specific, significantly activating the lectin complement pathway and restoring neutrophil degranulation.

Our data indicate that EVs are involved in diet-induced metabolic and inflammatory responses. Different EV populations may carry distinct sets of proteins involved in specific biological processes, thereby regulating diverse metabolic pathways efficiently.

Photobiomodulation (PBM), the use of biocompatible tissue-penetrating light to interact with intracellular chromophores to modulate the fates of cells and tissues, has emerged as a promising non-invasive approach to enhancing tissue regeneration. Unlike photodynamic or photothermal therapies that require the use of photothermal agents or photosensitizers, PBM treatment does not need external agents. With its non-harmful nature, PBM has demonstrated efficacy in enhancing molecular secretions and cellular functions relevant to tissue regeneration. The utilization of low-level light from various sources in PBM targets cytochrome c oxidase, leading to increased synthesis of adenosine triphosphate, induction of growth factor secretion, activation of signaling pathways, and promotion of direct or indirect gene expression. When integrated with stem cell populations, bioactive molecules or nanoparticles, or biomaterial scaffolds, PBM proves effective in significantly improving tissue regeneration. This review consolidates findings from in vitro, in vivo, and human clinical outcomes of both PBM alone and PBM-combined therapies in tissue regeneration applications. It encompasses the background of PBM invention, optimization of PBM parameters (such as wavelength, irradiation, and exposure time), and understanding of the mechanisms for PBM to enhance tissue regeneration. The comprehensive exploration concludes with insights into future directions and perspectives for the tissue regeneration applications of PBM.

Under vasculogenic conditioning, certain pro-inflammatory subsets within peripheral blood mononuclear cells (PBMCs) undergo phenotypic transformation into pro-regenerative types, such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells. These transformed cells are collectively termed regeneration-associated cells (RACs). In this study, we aimed to investigate the therapeutic efficacy of RAC-derived extracellular vesicles (RACev) compared with a vehicle-treated group in the context of renal ischemia-reperfusion injury (R-IRI). Human PBMCs were cultured with defined growth factor cocktails for seven days to harvest RACs. EV quantity and size were characterized by nanoparticle tracking analysis. Notably, the systemic injection of RACev significantly decreased serum creatinine and blood urine nitrogen at day three compared to the control group. Histologically, the treatment group showed less fibrosis in the cortex and medullary areas (p < 0.04 and p < 0.01) compared to the control group. The CD31 staining confirmed enhanced capillary densities in the treatment group compared to the control group (p < 0.003). These beneficial effects were accompanied by angiogenesis, anti-fibrosis, anti-inflammation, and anti-apoptosis RACev miR delivery to ischemic injury to control inflammatory, endothelial mesenchymal transition, and hypoxia pathways. In vivo bioluminescence analysis demonstrated a preferential accumulation of RACev in the IR-injured kidney. The systemic transplantation of RACev beneficially restored kidney function by protecting from tissue fibrosis and through anti-inflammation, angiogenesis, and anti-apoptosis miR delivery to the ischemic tissue.

Recent advancements in mesenchymal stem cell (MSC) technology have paved the way for innovative treatment options for various diseases. These stem cells play a crucial role in tissue regeneration and repair, releasing local anti-inflammatory and healing signals. However, challenges such as homing issues and tumorigenicity have led to exploring MSC-exosomes as a promising alternative. MSC-exosomes have shown therapeutic potential in conditions like renal ischemia-reperfusion injury, but low production yields hinder their clinical use.

To address this limitation, we examined hypoxic preconditioning of Wharton jelly-derived MSCs (WJ-MSCs) 3D-cultured in spheroids on isolated exosome yields and miR-21 expression. We then evaluated their capacity to load miR-210 into HEK-293 cells and mitigate ROS production, consequently enhancing their survival and migration under hypoxia-reoxygenation conditions.

MiR-210 overexpression was significantly induced by optimized culture and preconditioning conditions, which also improved the production yield of exosomes from grown MSCs. The exosomes enriched with miR-210 demonstrated a protective effect by improving survival, reducing apoptosis and ROS accumulation in damaged renal cells, and ultimately promoting cell migration.

The present study underscores the possibility of employing advanced techniques to maximize the therapeutic attributes of exosomes produced from WJ-MSC spheroid for improved recovery outcomes in ischemia-reperfusion injuries.

Extracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ‛cross-decoration'. In contrast, donor liver-derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant-relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti-inflammatory miRNA species. In terms of function, liver-derived EVs were able to cross-decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration-dependent fashion. In terms of cytokine response, the addition of 1 × 109 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF-α, IL-10 and IFN-γ. In conclusion, we determined physiologically produced liver-derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation.

Autoimmune diseases are caused by an imbalance in the immune system, producing autoantibodies that cause inflammation leading to tissue damage and organ dysfunction. Systemic Lupus Erythematosus (SLE) is one of the most common autoimmune diseases and a major contributor to patient morbidity and mortality. Although many drugs manage the disease, curative therapy remains elusive, and current treatment regimens have substantial side effects. Recently, the therapeutic potential of exosomes has been extensively studied, and novel evidence has been demonstrated. A direct relationship between exosome contents and their ability to regulate the immune system, inflammation, and angiogenesis. The unique properties of extracellular vesicles, such as biomolecule transportation, biodegradability, and stability, make exosomes a promising treatment candidate for autoimmune diseases, particularly SLE. This review summarizes the structural features of exosomes, the isolation/purification/quantification method, their origin, effect, immune regulation, a critical consideration for selecting an appropriate source, and their therapeutic mechanisms in SLE.

Cardiovascular diseases (CVDs) have emerged as a predominant threat to human health, surpassing the incidence and mortality rates of neoplastic diseases. Extracellular vesicles (EVs) serve as vital mediators in intercellular communication and material exchange. Endothelial progenitor cells (EPCs), recognized as precursors of vascular endothelial cells (ECs), have garnered considerable attention in recent years due to the potential therapeutic value of their derived extracellular vesicles (EPC-EVs) in the context of CVDs. This comprehensive review systematically explores the origins, characteristics, and functions of EPCs, alongside the classification, properties, biogenesis, and extraction techniques of EVs, with particular emphasis on their protective roles in CVDs. Additionally, we delve into the essential bioactive components of EPC-EVs, including microRNAs, long non-coding RNAs, and proteins, analyzing their beneficial effects in promoting angiogenesis, anti-inflammatory and anti-oxidant activities, anti-fibrosis, anti-apoptosis, and myocardial regeneration. Furthermore, this review comprehensively investigates the therapeutic potential of EPC-EVs across various CVDs, encompassing acute myocardial infarction, myocardial ischemia-reperfusion injury, atherosclerosis, non-ischemic cardiomyopathies, and diabetic cardiovascular disease. Lastly, we summarize the potential challenges associated with the clinical application of EPC-EVs and outline future directions, aiming to offer a valuable resource for both theoretical insights and practical applications of EPC-EVs in managing CVDs.

Pathological cardiac hypertrophy, characterized by the enlargement of cardiac muscle cells, leads to serious cardiac conditions and stands as a major global health issue. Exosomes, comprising small lipid bilayer vesicles, are produced by various cell types and found in numerous bodily fluids. They play a pivotal role in intercellular communication by transferring bioactive cargos to recipient cells or activating signaling pathways in target cells. Exosomes from cardiomyocytes, endothelial cells, fibroblasts, and stem cells are key in regulating processes like cardiac hypertrophy, cardiomyocyte survival, apoptosis, fibrosis, and angiogenesis within the context of cardiovascular diseases. This review delves into exosomes' roles in pathological cardiac hypertrophy, first elucidating their impact on cell communication and signaling pathways. It then advances to discuss how exosomes affect key hypertrophic processes, including metabolism, fibrosis, oxidative stress, and angiogenesis. The review culminates by evaluating the potential of exosomes as biomarkers and their significance in targeted therapeutic strategies, thus emphasizing their critical role in the pathophysiology and management of cardiac hypertrophy.

The imbalance between proliferation and death of kidney resident cells is a crucial factor in the development of acute or chronic renal dysfunction. Acute kidney injury (AKI) is often associated with the rapid loss of tubular epithelial cells (TECs). Sustained injury leads to the loss of glomerular endothelial cells (GECs) and podocytes, which is a key mechanism in the pathogenesis of glomerular diseases. This irreversible damage resulting from progressive cell loss eventually leads to deterioration of renal function characterized by glomerular compensatory hypertrophy, tubular degeneration, and renal fibrosis. Regulated cell death (RCD), which involves a cascade of gene expression events with tight structures, plays a certain role in regulating kidney health by determining the fate of kidney resident cells. Under pathological conditions, cells in the nephron have been demonstrated to constitutively release extracellular vesicles (EVs) which act as messengers that specifically interact with recipient cells to regulate their cell death process. For therapeutic intervention, exogenous EVs have exhibited great potential for the prevention and treatment of kidney disease by modulating RCD, with enhanced effects through engineering modification. Based on the functional role of EVs, this review comprehensively explores the regulation of RCD by EVs in AKI and chronic kidney disease (CKD), with emphasis on pathogenesis and therapeutic intervention.

Acute kidney injury (AKI) is a heterogeneous syndrome, comprising diverse etiologies of kidney insults that result in high mortality and morbidity if not well managed. Although great efforts have been made to investigate underlying pathogenic mechanisms of AKI, there are limited therapeutic strategies available. Extracellular vesicles (EV) are membrane-bound vesicles secreted by various cell types, which can serve as cell-free therapy through transfer of bioactive molecules. In this review, we first overview the AKI syndrome and EV biology, with a particular focus on the technical aspects and therapeutic application of cell culture-derived EVs. Second, we illustrate how multi-omic approaches to EV miRNA, protein, and genomic cargo analysis can yield new insights into their mechanisms of action and address unresolved questions in the field. We then summarize major experimental evidence regarding the therapeutic potential of EVs in AKI, which we subdivide into stem cell and non-stem cell-derived EVs. Finally, we highlight the challenges and opportunities related to the clinical translation of animal studies into human patients.

Psychological stress has been associated with the onset of several diseases, including osteoporosis. However, the underlying pathogenic mechanism remains unknown, and effective therapeutic strategies are still unavailable. Growing evidence suggests that the sympathetic nervous system regulates bone homeostasis and vascular function under psychological stress, as well as the coupling of osteogenesis and angiogenesis in bone development, remodeling, and regeneration. Furthermore, extracellular vesicles (EVs), particularly mesenchymal stem cell extracellular vesicles (MSC-EVs), have emerged as prospecting therapies for stimulating angiogenesis and bone regeneration. We summarize the role of sympathetic regulation in bone homeostasis and vascular function in response to psychological stress and emphasize the relationship between vessels and bone. Finally, we suggest using MSC-EVs as a promising therapeutic method for treating osteoporosis in psychological stress.

Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.

Most proteinuric dogs with naturally occurring chronic kidney disease have amyloidosis (AMYL), glomerulosclerosis (GS), or immune complex-mediated glomerulonephritis (ICGN), each with different treatment and prognosis. A noninvasive and disease-specific biomarker is lacking.

We hypothesized that the expression pattern of biofluid microRNA (miRNAs and miRs) would correlate with disease progression and categorization.

Archived serum and urine samples from 18 dogs with glomerular disease and 6 clinically healthy dogs; archived urine samples from 49 dogs with glomerular disease and 13 clinically healthy dogs.

Retrospective study. Archived biofluid samples from adult dogs with biopsy-confirmed glomerular disease submitted to the International Veterinary Renal Pathology Service between 2008 and 2016 were selected. Serum and urinary miRNAs were isolated and profiled using RNA sequencing. Urinary miR-126, miR-21, miR-182, and miR-486 were quantified using quantitative reverse transcription PCR.

When comparing more advanced disease with earlier disease, no serum miRNAs were differentially expressed, but urinary miR-21 and miR-182 were 1.63 (95% CI: .86-3.1) and 1.45 (95% CI: .82-2.6) times higher in azotemic dogs, respectively (adjusted P < .05) and weakly correlated with tubulointerstitial fibrosis (miR-21: r = .32, P = .03; miR-182: r = .28, P = .05). Expression of urinary miR-126 was 10.5 (95% CI: 4.1-26.7), 28.9 (95% CI: 10.5-79.8), and 126.2 (95% CI: 44.7-356.3) times higher in dogs with ICGN compared with dogs with GS, AMYL, and healthy controls, respectively (P < .001).

The miR-126 could help identify dogs that might benefit from immunosuppressive therapy in the absence of a biopsy. MiR-21 and miR-182 are potential markers of disease severity and fibrosis.

Mitochondria are multitasking organelles involved in maintaining the cell homoeostasis. Beyond its well-established role in cellular bioenergetics, mitochondria also function as signal organelles to propagate various cellular outcomes. However, mitochondria have a self-destructive arsenal of factors driving the development of diseases caused by mitochondrial dysfunction. Extracellular vesicles (EVs), a heterogeneous group of membranous nano-sized vesicles, are present in a variety of bodily fluids. EVs serve as mediators for intercellular interaction. Exosomes are a class of small EVs (30-100 nm) released by most cells. Exosomes carry various cargo including microRNAs (miRNAs), a class of short noncoding RNAs. Recent studies have closely associated exosomal miRNAs with various human diseases, including diseases caused by mitochondrial dysfunction, which are a group of complex multifactorial diseases and have not been comprehensively described. In this review, we first briefly introduce the characteristics of EVs. Then, we focus on possible mechanisms regarding exosome-mitochondria interaction through integrating signalling networks. Moreover, we summarize recent advances in the knowledge of the role of exosomal miRNAs in various diseases, describing how mitochondria are changed in disease status. Finally, we propose future research directions to provide a novel therapeutic strategy that could slow the disease progress mediated by mitochondrial dysfunction.

Apoptotic and healthy cells of domestic animals release membrane-enclosed particles from their plasma membrane. These special structures, called extracellular vesicles, play an important role in intercellular communication. In the past, it was believed that their function was mainly to dispose unwanted cell contents and to help maintain cell homeostasis. However, we now know that they have important roles in health and disease and have diagnostic value as well as great potential for therapy in veterinary medicine. Extracellular vesicles facilitate cellular exchanges by delivering functional cargo molecules to nearby or distant tissues. They are produced by various cell types and are found in all body fluids. Their cargo reflects the state of the releasing parent cell, and despite their small size, this cargo is extraordinarily complex. Numerous different types of molecules contained in vesicles make them an extremely promising tool in the field of regenerative veterinary medicine. To further increase research interest and discover their full potential, some of the basic biological mechanisms behind their function need to be better understood. Only then will we be able to maximize the clinical relevance for targeted diagnostic and therapeutic purposes in various domestic animal species.

The possible beneficial effects of stem cell-derived EV on ischemia-reperfusion injury (IRI) in organ transplantation have been frequently investigated; however, the source of EV, as well as the methods of isolation and administration vary widely. We conducted a systematic review to summarize current pre-clinical evidence on stem cell-derived EV therapy for IRI of transplantable organs.

PubMed, Embase and Web of Science were searched from inception until August 19th, 2022, for studies on stem cell-derived EV therapy for IRI after heart, kidney, liver, pancreas, lung and intestine transplantation. The Systematic Review Center for Laboratory animal Experiments (SYRCLE) guidelines were followed to assess potential risk of bias.

The search yielded 4153 unique articles, of which 96 were retained. We identified 32 studies on cardiac IRI, 38 studies on renal IRI, 21 studies on liver IRI, four studies on lung IRI and one study on intestinal IRI. Most studies used rodent models of transient ischemic injury followed by in situ reperfusion. In all studies, EV therapy was associated with improved outcome albeit to a variable degree. EV-therapy reduced organ injury and improved function while displaying anti-inflammatory-, immunomodulatory- and pro-regenerative properties.

A multitude of animal studies support the potential of stem cell-derived EV-therapy to alleviate IRI after solid organ transplantation but suffer from low reporting quality and wide methodological variability. Future studies should focus on determining optimal stem cell source, dosage, and timing of treatment, as well as long-term efficacy in transplant models.

Myocardial ischemia-reperfusion injury after myocardial infarction has always been a difficult problem in clinical practice. Endothelial cells and their secreted extracellular vesicles are closely related to inflammation, thrombosis formation, and other processes after injury. Meanwhile, low-molecular-weight gelators have shown great potential for nasal administration. This study aims to explore the therapeutic effects and significance of endothelial cell-derived extracellular vesicles combined with a hydrogel for nasal administration on myocardial ischemia-reperfusion injury.

We chose a gel system composed of a derivative of glutamine amide and benzaldehyde as the extracellular vesicle delivery vehicle. This hydrogel was combined with extracellular vesicles extracted from mouse aortic endothelial cells and administered multiple times intranasally in a mouse model of ischemia-reperfusion injury to the heart. The delivery efficiency of the extracellular vesicle-hydrogel combination was evaluated by flow cytometry and immunofluorescence. Echocardiography, TTC Evan's Blue and Masson's staining were used to assess mouse cardiac function, infarct area, and cardiac fibrosis level. Flow cytometry, ELISA, and immunofluorescence staining were used to investigate changes in mouse inflammatory cells, cytokines, and vascular neogenesis.

The vesicles combined with the hydrogel have good absorption in the nasal cavity. The hydrogel combined with vesicles reduces the levels of pro-inflammatory Ly6C (high) monocytes/macrophages and neutrophils. It can also reduce the formation of microcirculation thrombi in the infarcted area, improve endothelial barrier function, and increase microvascular density in the injured area. As a result, the heart function of mice is improved and the infarct area is reduced.

We first demonstrated that the combination of extracellular vesicles and hydrogel has a better absorption efficiency in the nasal cavity, which can improve myocardial ischemia-reperfusion injury by inhibiting inflammatory reactions and protecting endothelial function. Nasal administration of vesicles combined with hydrogel is a potential therapeutic direction.

High-density lipoproteins (HDL) play an established role in protecting against cellular dysfunction in a variety of different disease contexts; however, harnessing this therapeutic potential has proved challenging due to the heterogeneous and relative instability of this lipoprotein and its variable cargo molecules. The purpose of this study is to examine the contribution of microRNA (miRNA; miR) sequences, either delivered directly or modulated endogenously, to these protective functions. This narrative review introduces the complex cargo carried by HDL, the protective functions associated with this lipoprotein, and the factors governing biogenesis, export and the uptake of microRNA. The possible mechanisms by which HDL can modulate the cellular miRNA landscape are considered, and the impact of key sequences modified by HDL is explored in diseases such as inflammation and immunity, wound healing, angiogenesis, dyslipidaemia, atherosclerosis and coronary heart disease, potentially offering new routes for therapeutic intervention.

Renal ischemia-reperfusion injury (RIRI) is a complex disorder characterized by both intrinsic damage to renal tubular epithelial cells and extrinsic inflammation mediated by cytokines and immune cells. Unfortunately, there is no cure for this devastating condition. Extracellular vesicles (EVs) are nanosized membrane-bound vesicles secreted by various cell types that can transfer bioactive molecules to target cells and modulate their function. EVs have emerged as promising candidates for cell-free therapy of RIRI, owing to their ability to cross biological barriers and deliver protective signals to injured renal cells. In this review, we provide an overview of EVs, focusing on their functional role in RIRI and the signaling messengers responsible for EV-mediated crosstalk between various cell types in renal tissue. We also discuss the renoprotective role of EVs and their use as therapeutic agents for RIRI, highlighting the advantages and challenges encountered in the therapeutic application of EVs in renal disease.

Post-transcriptional regulation by non-coding RNAs (ncRNAs) can modulate the expression of genes involved in kidney physiology and disease. A large variety of ncRNA species exist, including microRNAs, long non-coding RNAs, piwi-interacting RNAs, small nucleolar RNAs, circular RNAs and yRNAs. Despite early assumptions that some of these species may exist as by-products of cell or tissue injury, a growing body of literature suggests that these ncRNAs are functional and participate in a variety of processes. Although they function intracellularly, ncRNAs are also present in the circulation, where they are carried by extracellular vesicles, ribonucleoprotein complexes or lipoprotein complexes such as HDL. These systemic, circulating ncRNAs are derived from specific cell types and can be directly transferred to a variety of cells, including endothelial cells of the vasculature and virtually any cell type in the kidney, thereby affecting the function of the host cell and/or its response to injury. Moreover, chronic kidney disease itself, as well as injury states associated with transplantation and allograft dysfunction, is associated with a shift in the distribution of circulating ncRNAs. These findings may provide opportunities for the identification of biomarkers with which to monitor disease progression and/or the development of therapeutic interventions.

Most cells in our body release membrane-bound, nano-sized particles into the extracellular milieu through cellular metabolic processes. Various types of macromolecules, reflecting the physiological and pathological status of the producing cells, are packaged into such so-called extracellular vesicles (EVs), which can travel over a distance to target cells, thereby transmitting donor cell information. The short, noncoding ribonucleic acid (RNA) called microRNA (miRNA) takes a crucial part in EV-resident macromolecules. Notably, EVs transferring miRNAs can induce alterations in the gene expression profiles of the recipient cells, through genetically instructed, base-pairing interaction between the miRNAs and their target cell messenger RNAs (mRNAs), resulting in either nucleolytic decay or translational halt of the engaged mRNAs. As in other body fluids, EVs released in urine, termed urinary EVs (uEVs), carry specific sets of miRNA molecules, which indicate either normal or diseased states of the kidney, the principal source of uEVs. Studies have therefore been directed to elucidate the contents and biological roles of miRNAs in uEVs and moreover to utilize the gene regulatory properties of miRNA cargos in ameliorating kidney diseases through their delivery via engineered EVs. We here review the fundamental principles of the biology of EVs and miRNA as well as our current understanding of the biological roles and applications of EV-loaded miRNAs in the kidney. We further discuss the limitations of contemporary research approaches, suggesting future directions to overcome the difficulties to advance both the basic biological understanding of miRNAs in EVs and their clinical applications in treating kidney diseases. © 2023 American Physiological Society. Compr Physiol 13:4833-4850, 2023.

Circulating endothelial progenitor cells (EPCs) play a pivotal role in the repair of diseases in which angiogenesis is required. Although they are a potentially valuable cell therapy tool, their clinical use remains limited due to suboptimal storage conditions and, especially, long-term immune rejection. EPC-derived extracellular vesicles (EPC-EVs) may be an alternative to EPCs given their key role in cell-cell communication and expression of the same parental markers. Here, we investigated the regenerative effects of umbilical cord blood (CB) EPC-EVs on CB-EPCs in vitro. After amplification, EPCs were cultured in a medium containing an EVs-depleted serum (EV-free medium). Then, EVs were isolated from the conditioned medium with tangential flow filtration (TFF). The regenerative effects of EVs on cells were investigated by analyzing cell migration, wound healing, and tube formation. We also analyzed their effects on endothelial cell inflammation and Nitric Oxide (NO) production. We showed that adding different doses of EPC-EVs on EPCs does not alter the basal expression of the endothelial cell markers nor change their proliferative potential and NO production level. Furthermore, we demonstrated that EPC-EVs, when used at a higher dose than the physiological dose, create a mild inflammatory condition that activates EPCs and boosts their regenerative features. Our results reveal for the first time that EPC-EVs, when used at a high dose, enhance EPC regenerative functions without altering their endothelial identity.

Extracellular vesicles (EVs) are cornerstones of intercellular communication with exciting fundamental, clinical, and more broadly biotechnological applications. However, variability in EV composition, which results from the culture conditions used to generate the EVs, poses significant fundamental and applied challenges and a hurdle for scalable bioprocessing. Thus, an understanding of the relationship between EV production (and for clinical applications, manufacturing) and EV composition is increasingly recognized as important and necessary. While chemical stimulation and culture conditions such as cell density are known to influence EV biology, the impact of biomechanical forces on the generation, properties, and biological activity of EVs remains poorly understood. Given the omnipresence of these forces in EV preparation and in biomanufacturing, expanding the understanding of their impact on EV composition-and thus, activity-is vital. Although several publications have examined EV preparation and bioprocessing and briefly discussed biomechanical stresses as variables of interest, this review represents the first comprehensive evaluation of the impact of such stresses on EV production, composition and biological activity. We review how EV biogenesis, cargo, efficacy, and uptake are uniquely affected by various types, magnitudes, and durations of biomechanical forces, identifying trends that emerge both generically and for individual cell types. We also describe implications for scalable bioprocessing, evaluating processes inherent in common EV production and isolation methods, and propose a path forward for rigorous EV quality control.

Renal ischemia-reperfusion injury (IRI) is a significant cause of acute kidney injury (AKI) and usually brings severe public health consequences. Adipose-derived endothelial progenitor cell (AdEPCs) transplantation is beneficial for AKI but suffers from low delivery efficiency. This study was conducted to explore the protective effects of magnetically delivered AdEPCs on the repair of renal IRI. Two types of magnetic delivery methods, namely the endocytosis magnetization (EM) method and the immunomagnetic (IM) method were fabricated using PEG@Fe₃O₄ and CD133@Fe₃O₄, and their cytotoxicities in AdEPCs were assessed. In the renal IRI rat model, magnetic AdEPCs were injected via the tail vein and a magnet was placed beside the injured kidney for magnetic guidance. The distribution of transplanted AdEPCs, renal function, and tubular damage were evaluated. Our results suggested that CD133@Fe₃O₄ had the minimum negative effects on the proliferation, apoptosis, angiogenesis, and migration of AdEPCs compared with PEG@Fe₃O₄. Renal magnetic guidance could significantly enhance the transplantation efficiency and the therapeutic outcomes of AdEPCs-PEG@Fe₃O₄ and AdEPCs-CD133@Fe₃O₄ in the injured kidneys. However, under renal magnetic guidance, AdEPCs-CD133@Fe₃O₄ had stronger therapeutic effects than PEG@Fe₃O₄ after renal IRI. The immunomagnetic delivery of AdEPCs with CD133@Fe₃O₄ could be a promising therapeutic strategy for renal IRI.

Aging is one of the key mechanisms of vascular dysfunction and contributes to the initiation and progression of ischemic stroke (IS). Our previous study demonstrated that ACE2 priming enhanced the protective effects of exosomes derived from endothelial progenitor cells (EPC-EXs) on hypoxia-induced injury in aging endothelial cells (ECs). Here, we aimed to investigate whether ACE2-enriched EPC-EXs (ACE2-EPC-EXs) could attenuate brain ischemic injury by inhibiting cerebral EC damage through their carried miR-17-5p and the underlying molecular mechanisms. The enriched miRs in ACE2-EPC-EXs were screened using the miR sequencing method. EPC-EXs, ACE2-EPC-EXs, and ACE2-EPC-EXs with miR-17-5p deficiency (ACE2-EPC-EXs^{antagomiR-17-5p}) were administered to transient middle cerebral artery occlusion (tMCAO)-operated aged mice or coincubated with hypoxia/reoxygenation (H/R)-treated aging ECs. The results showed that (1) the level of brain EPC-EXs and their carried ACE2 were significantly decreased in aged mice compared to in young mice, and (2) after tMCAO, aged mice displayed increases in brain cell senescence, infarct volume, and neurological deficit score (NDS) and a decrease in cerebral blood flow (CBF). (3) Compared with EPC-EXs, ACE2-EPC-EXs were enriched with miR-17-5p and more effective in increasing ACE2 and miR-17-5p expression in cerebral microvessels, accompanied by obvious increases in cerebral microvascular density (cMVD) and cerebral blood flow (CBF) and decreases in brain cell senescence, infarct volume, neurological deficit score (NDS), cerebral EC ROS production, and apoptosis in tMCAO-operated aged mice. Moreover, silencing of miR-17-5p partially abolished the beneficial effects of ACE2-EPC-EXs. (4) In H/R-treated aging ECs, ACE2-EPC-EXs were more effective than EPC-EXs in decreasing cell senescence, ROS production, and apoptosis and increasing cell viability and tube formation. In a mechanistic study, ACE2-EPC-EXs more effectively inhibited PTEN protein expression and increased the phosphorylation of PI3K and Akt, which were partially abolished by miR-17-5p knockdown. Altogether, our data suggest that ACE-EPC-EXs have better protective effects on ameliorating aged IS mouse brain neurovascular injury by inhibiting cell senescence, EC oxidative stress, apoptosis, and dysfunction by activating the miR-17-5p/PTEN/PI3K/Akt signaling pathway.

Endothelial progenitor cells (EPCs) are stem cells mainly derived from bone marrow; from where they migrate to repair and regenerate damaged tissues. eEPCs have been classified into two sub-populations, early (eEPC) and late EPCs (lEPC), depending on maturation stages in vitro. In addition, eEPC release endocrine mediators, including small extracellular vesicles (sEVs), which in turn may enhance the eEPC-mediated wound healing properties. Nevertheless, adenosine contributes to angiogenesis by recruiting eEPC at the injury site. However, whether ARs may enhance the secretome of eEPC, including sEVs, is unknown. Therefore, we aimed to investigate whether AR activation increase the release of sEVs in eEPC, which in turn has paracrine effects on recipient endothelial cells. Results shown that 5'-N-ethylcarboxamidoadenosine (NECA), a non-selective agonist, increase both the protein levels of the vascular endothelial growth factor (VEGF), and the number of sEVs released to the conditioned medium (CM) in primary culture of eEPC. Importantly, CM and EVs harvested from NECA-stimulated eEPC promote in vitro angiogenesis, without changes in cell proliferation, in recipient ECV-304 endothelial cells. This constitutes the first evidence showing that adenosine enhances sEVs release from eEPC, which has pro-angiogenic capacity on recipient endothelial cells.

Kidney disease management and treatment are currently causing a substantial global burden. The kidneys are the most important organs in the human urinary system, selectively filtering blood and metabolic waste into urine via the renal glomerulus. Based on charge and/or molecule size, the glomerular filtration apparatus acts as a barrier to therapeutic substances. Therefore, drug distribution to the kidneys is challenging, resulting in therapy failure in a variety of renal illnesses. Hence, different approaches to improve drug delivery across the glomerulus filtration barrier are being investigated. Nanotechnology in medicine has the potential to have a significant impact on human health, from illness prevention to diagnosis and treatment. Nanomaterials with various physicochemical properties, including size, charge, surface and shape, with unique biological attributes, such as low cytotoxicity, high cellular internalization and controllable biodistribution and pharmacokinetics, have demonstrated promising potential in renal therapy. Different types of nanosystems have been employed to deliver drugs to the kidneys. This review highlights the features of the nanomaterials, including the nanoparticles and corresponding hydrogels, in overcoming various barriers of drug delivery to the kidneys. The most common delivery sites and strategies of kidney-targeted drug delivery systems are also discussed.

Pathological cardiac hypertrophy is a well-recognized risk factor for cardiovascular diseases (CVDs). Although lots of efforts have been made to illustrate the underlying molecular mechanisms, many issues remain undiscovered. Recently, intercellular communication by delivering small molecules between different cell types in the progression of cardiac hypertrophy has been reported, including bioactive nucleic acids or proteins. These extracellular vesicles (EVs) may act in an autocrine or paracrine manner between cardiomyocytes and noncardiomyocytes to provoke or inhibit cardiac remodeling and hypertrophy. Besides, EVs can be used as novel diagnostic or prognostic biomarkers in cardiac hypertrophy and also may serve as potential therapeutic targets due to its biocompatible nature and low immunogenicity. In this chapter, we will first summarize the current knowledge about EVs from different cells in pathological cardiac hypertrophy. Then, we will focus on the value of EVs as therapeutic agents and biomarkers for pathological myocardial hypertrophy.

Extracellular vesicles (EVs) are nanoscale membranous vesicles containing DNA, RNA, lipids, and proteins, which play versatile roles in intercellular communications. EVs are increasingly being recognized as the promising therapeutic agents for many diseases, including cardiocerebrovascular and metabolic diseases, due to their ability to deliver functional and therapeutical molecules. In this chapter, the biological characteristics and functions of EVs are briefly summarized. Importantly, the current state of applying EVs in the prevention and treatment of cardiocerebrovascular and metabolic diseases, including myocardial infarction, atrial fibrillation, myocardial hypertrophy, stroke, diabetes, Alzheimer's disease, fatty liver, obesity, thyroid diseases, and osteoporosis, is discussed. Lastly, the challenges and prospects related to the preclinical and clinical application of EVs receive a particular focus.

The rising global incidence of acute and chronic kidney diseases has increased the demand for renal replacement therapy. This issue, compounded with the limited availability of viable kidneys for transplantation, has propelled the search for alternative strategies to address the growing health and economic burdens associated with these conditions. In the search for such alternatives, significant efforts have been devised to augment the current and primarily supportive management of renal injury with novel regenerative strategies. For example, gene- and cell-based approaches that utilize recombinant peptides/proteins, gene, cell, organoid, and RNAi technologies have shown promising outcomes primarily in experimental models. Supporting research has also been conducted to improve our understanding of the critical aspects that facilitate the development of efficient gene- and cell-based techniques that the complex structure of the kidney has traditionally limited. This manuscript is intended to communicate efforts that have driven the development of such therapies by identifying the vectors and delivery routes needed to drive exogenous transgene incorporation that may support the treatment of acute and chronic kidney diseases.

Neural progenitor cells (NPCs) and endothelial progenitor cell (EPCs) exhibit synergistical effects on protecting endothelial cell functions. MiR-126 and miR-210 can protect cell activities by regulating brain-derived neurotrophic factor (BDNF) and reactive oxygen species (ROS) production. Exosomes (EXs) mediate the beneficial effects of stem cells via delivering microRNAs (miRs). Here, we investigated the combination effects of EXs from EPCs (EPC-EXs) and NPCs (NPC-EXs), and determined whether these EXs with miR-126 (EPC-EXs^miR-126) and miR-210 overexpression (NPC-EXs^miR-210) had better effects on hypoxia/reoxygenation (H/R)-injured neurons and ischemic stroke (IS).

Cultured neurons were subjected to hypoxia for 6 h and then co-cultured with culture medium, NPC-EXs, EPC-EXs, NPC-EXs + EPC-EXs or NPC-EXs^miR-210 + EPC-EXs^miR-126 under normoxia for 24 h. Cell apoptosis, ROS production, neurite outgrowth and BDNF level were analyzed. Permanent middle cerebral artery occlusion (MCAO) was performed on C57BL/6 mice to build IS model. The mice were injected with PBS or various EXs via tail vein 2 h after MCAO operation. After 24 h, infarct volume and neurological deficits score (NDS), neuronal apoptosis, ROS production and spine density of dendrites, and brain BDNF level were analyzed. For mechanism study, NADPH oxidase 2(Nox2) and BDNF receptor tyrosine kinase receptor B (TrkB) were determined, and TrkB inhibitor k-252a was used in in vitro and in vivo study.

1) The level of miR-210 or miR-126 was increased after NPC-EXs or EPC-EXs treatment respectively. 2) In H/R-injured neurons, NPC-EXs or EPC-EXs decreased cell apoptosis and ROS production and promoted neurite outgrowth, which were associated with the downregulation of Nox2 and the increase of BDNF and p-TrkB/TrkB level. 3) In MCAO mice, NPC-EXs or EPC-EXs decreased infarct volume and NDS, reduced neural apoptosis and ROS production, and promoted the spine density of dendrites. The levels of Nox2, BDNF and p-TrkB/TrkB in mouse brain tissues changed in similar patterns as seen in the in vitro study. 4) In both cell and mouse models, combination of NPC-EXs and EPC-EXs was more effective than NPC-EXs or EPC-EXs alone on all of these effects. 5) EPC-EXs^miR-126 + NPC-EXs^miR-210 had better effects compared to NPC-EXs + EPC-EXs, which were inhibited by k-252a.

EPC-EXs^miR-126 combined NPC-EXs^miR-210 further orchestrate the combinative protective effects of EPC-EXs and NPC-EXs on IS, possibly by protecting H/R-injured neurons through the Nox2/ ROS and BDNF/TrkB pathways.

The incidence of renal disease is gradually increasing worldwide, and this condition has become a major public health problem because it is a trigger for many other chronic diseases. Cell therapies using multipotent mesenchymal stromal cells, hematopoietic stem cells, macrophages, and other cell types have been used to induce regeneration and provide a cure for acute and chronic kidney disease in experimental models. This review describes the advances in cell therapy protocols applied to acute and chronic kidney injuries and the attempts to apply these treatments in a clinical setting.

Our previous study showed that oscillatory shear stress (OSS) induces endothelial progenitor cells (EPCs) to undergo endothelial to mesenchymal transition (EndoMT), which may contribute to the onset and progression of atherosclerosis (AS). However, the underlying mechanisms have not been elucidated. A recent study showed that exosomes (Exos) released from EPCs played a key role in various cardiovascular diseases. The purpose of this study was to identify the role and mechanism of Exos released by EPCs exposed to OSS in EPC EndoMT.

EPCs derived from the human umbilical cord blood were cultured and characterized. The Flexcell flow STR-4000 parallel plate flow chamber system was employed to apply OSS (±3.5 dyne/cm², 1 Hz) to EPCs for 12 h. Then, Exos were extracted from the cellular supernatant (Static-Exos) or perfusate (OSS-Exos) by exoEasy Maxi Kit. Afterward, cellular intervention, angiogenesis assays, high-throughput sequencing and online database predictions were used to identify the role and mechanism of OSS-Exos in EPC EndoMT.

OSS-Exos inhibited angiogenesis, promoted the proliferation of EPCs both in vivo and in vitro, and induced EPC EndoMT. In addition, the expression of circ-1199 in OSS-Exos was higher than that in Static-Exos. Moreover, circ-1199 induced EPC EndoMT. The dual-luciferase reporter gene assay showed that let-7g-5p was the direct target of circ-1199. Furthermore, OSS-Exos upregulated the expression of circ-1199 and then downregulated let-7g-5p, upregulating HMGA2, which activated p-Smad3/Smad3 and Snail.

OSS-Exos played an important role in the EndoMT of EPCs, which was mediated by the circ-1199/let-7g-5p/HMGA2 signaling pathway. These studies would have a high probability of revealing the mechanism of EPC EndoMT.

Extracellular Vesicles (EVs) are circulating particles surrounded by a plasma membrane carrying a cargo consisting of proteins, lipids, RNAs, and DNA fragments, stemming from the cells from which they originated. EV factors (i.e., miRNAs) play relevant roles in intercellular crosstalk, both locally and systemically. As EVs increasingly gained attention as potential carriers for targeted genes, the study of EV effects on the host immune response became more relevant. It has been demonstrated that EVs regulate the host immune response, executing both pro- and anti-inflammatory functions. It is also known that physical exercise triggers anti-inflammatory effects. This review underlines the role of circulating EVs as players in the anti-inflammatory events associated with the regulation of the host's immune response to physical exercise.

Acute kidney injury (AKI) induced by ischemia/reperfusion injury significantly contribute to the burden of end-stage renal disease. Extracellular vesicles (EVs), especially for stem/progenitor cell-derived EVs (stem/progenitor cell-EVs), have emerged as a promising therapy for ischemia/reperfusion injury-induced AKI. However, their regulatory effects remain poorly understood, and their therapeutic efficiency in clinical trials is controversial. Here, we performed this systematic review and meta-analysis to assess the stem/progenitor cell-EV efficacy in treating ischemia/reperfusion injury-induced AKI in preclinical rodent models.

A literature search was performed in PubMed, Embase, Scopus, and Web of Science to identify controlled studies about the therapeutic efficiency of stem/progenitor cell-EVs on ischemia/reperfusion injury-induced AKI rodent models. The level of SCr, an indicator of renal function, was regarded as the primary outcome. Meta-regression analysis was used to reveal the influential factors of EV therapy. Sensitivity analysis, cumulative meta-analysis, and assessment of publication bias were also performed in our systematic review and meta-analysis. A standardized mean difference (SMD) was used as the common effect size between stem/progenitor cell-EV-treated and control groups, with values of 0.2, 0.5, 0.8, and 1.0 defined as small, medium, large, and very large effect sizes, respectively.

A total of 30 studies with 985 ischemia/reperfusion injury-induced AKI rodent models were included. The pooled results showed that EV injection could lead to a remarkable sCr reduction compared with the control group (SMD, - 3.47; 95%CI, - 4.15 to - 2.80; P < 0.001). Meanwhile, the EV treatment group had lower levels of BUN (SMD, - 3.60; 95%CI, - 4.25 to - 2.94; P < 0.001), indexes for tubular and endothelial injury, renal fibrosis (fibrosis score and α-SMA), renal inflammation (TNF-α, IL-1β, iNOS, and CD68 + macrophages), but higher levels of indexes for tubular proliferation, angiogenesis-related VEGF, and reactive oxygen species. However, our meta-regression analysis did not identify significant associations between sCr level and cell origins of EVs, injection doses, delivery routes, and therapy and outcome measurement time (all P values > 0.05). Significant publication bias was observed (Egger's test, P < 0.001).

Stem/progenitor cell-EVs are effective in improving renal function in rodent ischemia/reperfusion injury-induced AKI model. These vesicles may help (i) reduce cell apoptosis and stimulate cell proliferation, (ii) ameliorate inflammatory injury and renal fibrosis, (iii) promote angiogenesis, and (iv) inhibit oxidative stress. However, the current systematic review and meta-analysis did not identify significant influential factors associated with treatment effects. More preclinical studies and thoughtfully designed animal studies are needed in the future.

Intravenous adipose mesenchymal stem cells (ADSCs) attenuate renal ischemia/reperfusion (IR) injury but with major drawbacks, including the lack of a specific homing effect after systemic infusion, cell trapping in the lung, and early cell death in the damaged microenvironment. We examined whether intrarenal arterial transplantation of dexmedetomidine (DEX) preconditioning ADSC-derived microvesicles (DEX-MVs) could promote further therapeutic potential to reduce renal IR injury. We evaluated the effect of DEX-MVs on NRK-52E cells migration, hypoxia/reoxygenation (H/R)-induced cell death, and reactive oxygen species (ROS) amount and renal IR model in rats. IR was established by bilateral 45 min ischemia followed by 4 h reperfusion. Intrarenal MVs or DEX-MVs were administered prior to ischemia. Renal oxidative stress, hemodynamics and function, western blot, immunohistochemistry, and tubular injury scores were determined. The miR-122-5p expression in kidneys was analyzed using microarrays and quantitative RT-PCR and its action target was predicted by TargetScan. DEX-MVs were more efficient than MVs to increase migration capability and to further decrease H/R-induced cell death and ROS level in NRK-52E cells. Consistently, DEX-MVs were better than MV in increasing CD44 expression, improving IR-depressed renal hemodynamics and renal erythropoietin expression, inhibiting IR-enhanced renal ROS level, tubular injury score, miR-122-5p expression, pNF-κB expression, Bax/caspase 3/poly(ADP-ribose) polymerase (PARP)-mediated apoptosis, blood urea nitrogen, and creatinine levels. The use of NRK-52E cells confirmed that miR-122-5p mimic via inhibiting erythropoietin expression exacerbated Bax-mediated apoptosis, whereas miR-122-5p inhibitor via upregulating erythropoietin and Bcl-2 expression reduced apoptosis. In summary, intrarenal arterial DEX-MV conferred further therapeutic potential to reduce renal IR injury through the miR-122-5p/erythropoietin/apoptosis axis.