Stem cell extracellular vesicles (EVs) have been widely studied because of their excellent therapeutic potential. EVs from different types of stem cell can improve vascularization as well as aid in the treatment of cancer and neurodegenerative diseases. The skin is a complex organ that is susceptible to various types of injury. Strategies designed to restore epithelial tissues’ integrity with stem cell EVs have shown promising results. Different populations of stem cell EVs are able to control inflammation, accelerate skin cell migration and proliferation, control wound scarring, improve angiogenesis, and even ameliorate signs of skin aging. However, large-scale production of such stem cell EVs for human therapy is still a challenge. This review focuses on recent studies that explore the potential of stem cell EVs in skin wound healing and skin rejuvenation, as well as challenges of their use in therapy.

Extracellular vesicles (EVs)/exosomes are nanosized membrane-bound structures that are released by virtually all cells. EVs have attracted great attention in the scientific community since the discovery of their roles in cell-to-cell communication. EVs’ enclosed structure protects bioactive molecules from degradation in the extracellular space and targets specific tissues according to the topography of membrane proteins. Upon absorption by recipient cells, EV cargo can modify the transcription machinery and alter the cellular functions of these cells, playing a role in disease pathogenesis. EVs have been tested as the delivery system for the mRNA COVID-19 vaccine. Recently, different therapeutic strategies have been designed to use EVs as a delivery system for microRNAs and mRNA. In this review, we will focus on the exciting and various platforms related to using EVs as delivery vehicles, mainly in gene editing using CRISPR/Cas9, cancer therapy, drug delivery, and vaccines. We will also touch upon their roles in disease pathogenesis.

People living with HIV (PLHIV) are at a higher risk of having cerebrocardiovascular diseases (CVD) compared to HIV negative (HIV^neg) individuals. The mechanisms underlying this elevated risk remains elusive. We hypothesize that HIV infection results in modified microRNA (miR) content in plasma extracellular vesicles (EVs), which modulates the functionality of vascular repairing cells, i.e., endothelial colony-forming cells (ECFCs) in humans or lineage negative bone marrow cells (lin⁻ BMCs) in mice, and vascular wall cells. PLHIV (N = 74) have increased atherosclerosis and fewer ECFCs than HIV^neg individuals (N = 23). Plasma from PLHIV was fractionated into EVs (HIV^posEVs) and plasma depleted of EVs (HIV PL^depEVs). HIV^posEVs, but not HIV PL^depEVs or HIV^negEVs (EVs from HIV^neg individuals), increased atherosclerosis in apoE^−/− mice, which was accompanied by elevated senescence and impaired functionality of arterial cells and lin⁻ BMCs. Small RNA-seq identified EV-miRs overrepresented in HIV^posEVs, including let-7b-5p. MSC (mesenchymal stromal cell)-derived tailored EVs (TEVs) loaded with the antagomir for let-7b-5p (miRZip-let-7b) counteracted, while TEVs loaded with let-7b-5p recapitulated the effects of HIV^posEVs in vivo. Lin⁻ BMCs overexpressing Hmga2 (a let-7b-5p target gene) lacking the 3′UTR and as such is resistant to miR-mediated regulation showed protection against HIV^posEVs-induced changes in lin⁻ BMCs in vitro. Our data provide a mechanism to explain, at least in part, the increased CVD risk seen in PLHIV.

EPCs play important roles in the maintenance of vascular repair and health. Aging is associated with both reduced numbers and functional impairment of EPCs, leading to diminished angiogenic capacity, impaired cardiac repair, and increased risk for cardiovascular disease (CVD). The molecular mechanisms that govern EPC function in cardiovascular health are not fully understood, but there is increasing evidence that microRNAs (miRNAs) play key roles in modulating EPC functionality, endothelial homeostasis, and vascular repair. We aimed to determine how aging alters endothelial progenitor (EPC) health and functionality by altering key miRNA-mRNA pathways. To identify key miRNA-mRNA pathways contributing to diminished EPC functionality associated with aging, microRNA and mRNA profiling were conducted in EPCs from young and aged C57BL/6 mice. We identified a complex aging-associated regulatory network involving two miRNAs—miR-29c-3p and -126a—that acted in tandem to impair vascular endothelial growth factor signaling through targeting Klf2 and Spred1, respectively. The modulation of components of the miR-29c-3p–Klf2–miR-126a–Spred-1–Vegf signaling pathway altered EPC self-renewal capacity, vascular tube formation, and migration in vitro, as well as cardiac repair in vivo. The miR-29c-3p–Klf2–miR-126a–Spred1–Vegf signaling axis plays a critical role in regulating the aging-associated deficits in EPC-mediated vascular repair and CVD risk.

Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. In this study, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. In vitro, cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, smooth muscle-specific overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Thus, miR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of the miR-423-5p—Cacna2d2—Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced HTN and aortic stiffness.