Mesenchymal Stem Cell-Derived Extracellular Vesicles as Proposed Therapy in a Rat Model of Cerebral Small Vessel Disease

Abstract

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been employed in the past decade as therapeutic agents in various diseases, including central nervous system (CNS) disorders. We currently aimed to use MSC-EVs as potential treatment for cerebral small vessel disease (CSVD), a complex disorder with a variety of manifestations. MSC-EVs were intranasally administrated to salt-sensitive hypertension prone SBH/y rats that were DOCA-salt loaded (SBH/y-DS), which we have previously shown is a model of CSVD. MSC-EVs accumulated within brain lesion sites of SBH/y-DS. An in vitro model of an inflammatory environment in the brain demonstrated anti-inflammatory properties of MSC-EVs. Following in vivo MSC-EV treatment, gene set enrichment analysis (GSEA) of SBH/y-DS cortices revealed downregulation of immune system response-related gene sets. In addition, MSC-EVs downregulated gene sets related to apoptosis, wound healing and coagulation, and upregulated gene sets associated with synaptic signaling and cognition. While no specific gene was markedly altered upon treatment, the synergistic effect of all gene alternations was sufficient to increase animal survival and improve the neurological state of affected SBH/y-DS rats. Our data suggest MSC-EVs act as microenvironment modulators, through various molecular pathways. We conclude that MSC-EVs may serve as beneficial therapeutic measure for multifactorial disorders, such as CSVD.

Unraveling the gut microbiota's role in salt-sensitive hypertension: current evidences and future directions

“…This can impact the development of SSH by affecting the activity of TH17 cells through various mechanisms involving the gut flora ( 13 , 38 , 39 ). Extracellular vesicles (EVs) play a crucial role in SSH by transporting proteins, nucleic acids, and lipids among cells ( 41 ). Urinary EVs are being researched as possible biomarkers for hypertension, as they contain proteins related to renal sodium transport, which is important in hypertension development ( 42 ).…”

“…Higher levels of NCC or phosphorylated NCC in urinary EVs are found in hypertensive patients, indicating the importance of EVs in hypertension. Other markers linked to hypertension, like Inducible Vitamin D Gene 2 protein and hsa-miR-4516, have also been identified in EVs, showing potential for early detection of hypertension ( 41 – 44 ). Thus, the gut microbiota may affect blood pressure in SSH by controlling salt absorption and metabolism through extracellular vesicles, potentially worsening the condition.…”

Insight into extracellular vesicles in vascular diseases: intercellular communication role and clinical application potential

“…MSC-EVs decrease IL-1β and IL-6 expression in lipopolysaccharides-stimulated BV2 cells and attenuate inflammation [ 64 ]. Researchers built animal models of CSVD using salt-loaded SBH/y rats to induce hypertension and found that cognitive deficits improved after MSC-EV treatment [ 64 ]. However, the underlying mechanisms require further in-depth studies [ 64 ].…”

“…Researchers built animal models of CSVD using salt-loaded SBH/y rats to induce hypertension and found that cognitive deficits improved after MSC-EV treatment [ 64 ]. However, the underlying mechanisms require further in-depth studies [ 64 ]. Most studies have focused on EVs from the serum or plasma of patients and healthy volunteers as diagnostic markers for CSVD; however, a large gap exists in the understanding of the pathological roles and therapeutic potential of EVs in this disease.…”

Extracellular vesicles as biomarkers and modulators of atherosclerosis pathogenesis

“…Several studies have used the rat model to study the role of EVs in spinal cord injuries (143,144) and repetitive stress (145). Rat models have also been used to investigate the therapeutic potential of EVs to treat diseases such as small cerebral vessel disease (146), colo-cutaneous post-surgical fistula (147), and congenital diaphragmatic hernia (148).…”