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Background: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ischemic stroke and systemic cancer are two of the leading causes of mortality. Hypoxia is a central pathophysiological component in ischemic stroke and cancer, representing a joint medical function. This function includes angiogenesis regulation. Vascular remodeling coupled with axonal outgrowth following cerebral ischemia is critical in improving poststroke neurological functional recovery. Antiangiogenic strategies can inhibit cancer vascularization and play a vital role in impeding cancer growth, invasion, and metastasis. Although there are significant differences in the cause of angiogenesis across both pathophysiological conditions, emerging evidence states that common signaling structures, such as extracellular vesicles (EVs) and noncoding RNAs (ncRNAs), are involved in this context. EVs, heterogeneous membrane vesicles encapsulating proteomic genetic information from parental cells, act as multifunctional regulators of intercellular communication. Among the multifaceted roles in modulating biological responses, exhaustive evidence shows that ncRNAs are selectively sorted into EVs, modulating common specific aspects of cancer development and stroke prognosis, namely, angiogenesis. This review will discuss recent advancements in the EV-facilitated/inhibited progression of specific elements of angiogenesis with a particular concern about ncRNAs within these vesicles. The review is concluded by underlining the clinical opportunities of EV-derived ncRNAs as diagnostic, prognostic, and therapeutic agents., (© 2023 Wiley-VCH GmbH.)

Hypoxia is a central pathophysiological component in cancer, myocardial infarction and ischemic stroke, which represent the most common medical conditions resulting in long-term disability and death. Recent evidence suggests common signaling pathways in these diverse settings mediated by non-coding RNAs (ncRNAs), which are packaged in extracellular vesicles (EVs) protecting ncRNAs from degradation. EVs are a heterogeneous group of lipid bilayer-covered vesicles released from virtually all cells, which have important roles in intercellular communication. Recent studies pointed out that ncRNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are selectively sorted into EVs, modulating specific aspects of cancer development, namely cell proliferation, migration, invasion, angiogenesis, immune tolerance or drug resistance, under conditions of hypoxia in recipient cells. In myocardial infarction and stroke, ncRNAs shuttled via EVs have been shown to control tissue survival and remodeling post-hypoxia by regulating cell injury, inflammatory responses, angiogenesis, neurogenesis or neuronal plasticity. This review discusses recent evidence on EV-associated ncRNAs in hypoxic cancer, myocardial infarction and stroke, discussing their cellular origin, biological function and disease significance. The emerging concept of lncRNA-circular RNA/ miRNA/ mRNA networks is outlined, upon which ncRNAs synergistically respond to hypoxia in order to modify disease responses. Particular notion is given to ncRNAs participating in at least two of the three conditions, which revealed a large degree of overlaps across pathophysiological conditions. Possible roles of EV-ncRNAs as therapeutic products or theranostic markers are defined., Competing Interests: Competing Interests: D.M.H., B.G. and T.R.D. hold a patent on extracellular vesicles for the treatment of inflammatory conditions (US9877989B2)., (© The author(s).)

Pulmonary fibrosis is a type of chronic, progressive, fibrotic lung disease of unclear cause with few treatment options. Cell therapy is emerging as a promising novel modality for facilitating lung repair. Mesenchymal stem cell (MSC)-based and macrophage-based cell therapies are regarded as promising strategies to promote lung repair, due to incredible regenerative potential and typical immunomodulatory function, respectively. Extracellular vesicles (EVs), including exosomes and microvesicles, are cell-derived lipid-bilayer membrane vesicles that are secreted from virtually every cell and are involved in intercellular communication by delivering expansive biological cargos to recipients. This review provides a deep insight into the recent research progress concerning the effects of MSC and macrophage-associated EVs on the pathogenesis of pulmonary fibrosis. In addition to discussing their respective vital roles, we summarize the importance of cross-talk, as macrophages are vital for MSCs to exert their protective effects through two major patterns, including attenuating macrophage activation and M1 phenotype macrophage polarization. Moreover, miRNAs are selectively enriched into EVs as essential components, and consideration is given to the particular effects of EV-associated miRNAs. [ABSTRACT FROM AUTHOR]

Eukaryotic cells release different types of extracellular vesicles (EVs), including exosomes, apoptotic bodies and microvesicles. EVs carry proteins, lipids and nucleic acids specific to cells and cell states. Autophagy is an intracellular degradation process, which, along with EVs, can significantly affect the development and progression of neurological diseases and, therefore, has been the hotspot. Generally, EVs and autophagy are closely associated. EVs and autophagy can interact with each other. On the one hand, the level of autophagy in target cells is closely related to the secretion and transport of EVs. In another, the application of EVs provides a great opportunity for adjuvant treatment of neurological disorders, for which autophagy is an excellent target. EVs can release their cargos into target cells, which, in turn, regulate the autophagic level of target cells through autophagy-related proteins directly and the non-coding RNA, signal transducer and activator of transcription 3 (STAT3), phosphodiesterase enzyme (PDE) 1-B, etc. signaling pathways indirectly, thus regulating the development of related neurological disorders. [ABSTRACT FROM AUTHOR]

Neurons and neurogliocytes (oligodendrocytes, astrocytes, and microglia) are essential for maintaining homeostasis of the microenvironment in the central nervous system (CNS). These cells have been shown to support cell-cell communication via multiple mechanisms, most recently by the release of extracellular vesicles (EVs). Since EVs carry a variety of cargoes of nucleic acids, lipids, and proteins and mediate intercellular communication, they have been the hotspot of diagnosis and treatment. The mechanisms underlying CNS disorders include angiogenesis, autophagy, apoptosis, cell death, and inflammation, and cell-EVs have been revealed to be involved in these pathological processes. Ischemic stroke is one of the most common causes of death and disability worldwide. It results in serious neurological and physical dysfunction and even leads to heavy economic and social burdens. Although a large number of researchers have reported that EVs derived from these cells play a vital role in regulating multiple pathological mechanisms in ischemic stroke, the specific interactional relationships and mechanisms between specific cell-EVs and stroke treatment have not been clearly described. This review aims to summarize the therapeutic effects and mechanisms of action of specific cell-EVs on ischemia. Additionally, this study emphasizes that these EVs are involved in stroke treatment by inhibiting and activating various signaling pathways such as ncRNAs, TGF-β1, and NF-κB. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a whole joint disease characterized by synovitis, cartilage destruction, and subchondral bone sclerosis and cyst. Despite decades' study, effective treatment is rare for this chronic disease. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptosis bodies, are nano-sized vesicles with a cargo containing biologically active agents, such as nucleic acids, lipids, and proteins. As a group of short non-coding RNAs, microRNAs (miRNAs) can be delivered by parental cells secreted EVs. Negatively regulate the target mRNAs at the posttranscriptional level and regulate gene expression in recipient cells without modifying gene sequence. Recently, most studies focused on the function of EVs mediated miRNAs in the pathophysiological process of OA. However, all kinds of EVs specific and OA specific factors might influence the administration of EVs-miRNAs, especially the precise quantitative management. As a result, the flourishing of current research about EVs in the laboratory might not promote the relevant clinical transformation in OA treatment. In this review, we reviewed the present application of EVs-miRNAs in the therapeutic of OA and further analyzed the potential factors that might influence its application. Further progress in the quantitative management of EVs-miRNAs would accelerate the clinical transformation of miRNAs enriched EVs in the OA field. [ABSTRACT FROM AUTHOR]