Stem cell‐derived extracellular vesicles mitigate ageing‐associated arterial stiffness and hypertension

Abstract

The prevalence of arterial stiffness and hypertension increases with age. This study investigates the effect of induced pluripotent mesenchymal stem cell-derived extracellular vesicles (EVs) on ageing-associated arterial stiffness and hypertension. EVs were collected and purified from induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs). Young and old male C57BL/6 mice were used. Mice in the EVs group were injected via tail vein once a week for four weeks (18 x 10 6 EVs/mouse/injection). Blood pressure (BP) was measured using the tail-cuff method and validated by direct cannulation. Pulse wave velocity (PWV) was measured using a Doppler workstation. PWV and BP were increased significantly in the old mice, indicating arterial stiffness and hypertension. Intravenous administration of EVs significantly attenuated ageing-related arterial stiffness and hypertension, while enhancing endothelium-dependent vascular relaxation and arterial compliance in the old EVs mice. Elastin degradation and collagen I deposition (fibrosis) were increased in aortas of the old mice, but EVs substantially improved ageing-associated structural remodelling. Mechanistically, EVs abolished downregulation of sirtuin type 1 (SIRT1), and endothelial nitric oxide synthase (eNOS) protein expression in aortas of the older mice. In cultured human aortic endothelial cells, EVs promoted the expression of SIRT1, AMP-activated protein kinase alpha (AMPKα), and eNOS. In conclusion, iPS-MSC-derived EVs attenuated ageing-associated vascular endothelial dysfunction, arterial stiffness, and hypertension, likely via activation of the SIRT1-AMPKα-eNOS pathway and inhibition of MMPs and elastase. Thus, EVs mitigate arterial ageing. This finding also sheds light into the therapeutic potential of EVs for ageing-related vascular diseases.

Exploring the utility of extracellular vesicles in ameliorating viral infection-associated inflammation, cytokine storm and tissue damage

“…In the human body, tissue repair activities are carried out by various types of stromal and progenitor cells [ 68 , 69 ]. EVs released by these stromal cells regulate many key biological functions, such as immunomodulatory activities, tissue regeneration processes, and their involvement in spreading viral infections [ 70 , 71 ]. EVs are therapeutic agents that are able to stimulate the regulation of tissue repair and remodeling activities [72] .…”

Diagnostic and Therapeutic Potential of Extracellular Vesicles

“… 22 , 54 Immune affinity-based isolation uses antibodies to capture EVs. 22 , 56 This method is not a cost-effective approach. Table 1 .…”

“… 10 Microvesicles are released by outward vesiculation of the cell membrane. 10 , 22 Exosomes are formed by endocytosis of cell membrane forming microvesicular bodies (MVBs). 23 , 24 These MVBs fuse with the plasma membrane and are released into the extracellular space.…”

CD9, a tetraspanin target for cancer therapy?

“…93,94 EVs are implicated in intercellular communication in both healthy and disease states. [95][96][97][98] They act as vehicles for the intercellular transfer of bioactive membranous and cytosolic molecules such as proteins, lipids, and various types of RNAs. [99][100][101] EVs can be isolated from various body fluids such as blood, urine, saliva, tears, seminal fluid, cerebrospinal fluid, and malignant ascites.…”