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Dysfunctional Mesenchymal Stem Cell-derived Extracellular Vesicles in Chronic Kidney Disease: A Role in Vascular Calcification

ABSTRACT: Background: Vascular calcification (VC) is a severe complication of chronic kidney disease (CKD) and increases cardiovascular morbidity and mortality. Extracellular vesicles (EVs) from bone mesenchymal stem cells (BMSCs) may influence vascular health through intercellular communication. This study investigated how CKD alters the anti-calcific function of BMSC-derived EVs, focusing on microRNA content, particularly miR-29a-3p. Methods: EVs were isolated from healthy and CKD-affected BMSCs and assessed for size, uptake by vascular smooth muscle cells (VSMCs), and miRNA content. High-phosphate-treated VSMCs and CKD rat models of vascular calcification were used to evaluate the effects of EVs on VC. Circulating miR-29a-3p was measured in hemodialysis patients and correlated with VC severity. Results: EVs from both groups showed comparable size and VSMC uptake. However, CKD-derived EVs had an altered miRNA profile, including markedly reduced miR-29a-3p, and showed diminished ability to inhibit phosphate-induced calcification. Restoration of miR-29a-3p suppressed calcification in vitro and in vivo. In hemodialysis patients, circulating miR-29a-3p was inversely associated with calcification severity. Conclusions: CKD impairs the anti-calcific function of BMSC-derived EVs partly through downregulation of EV-associated miR-29a-3p. Restoring miR-29a-3p may help mitigate VC in CKD, and circulating miR-29a-3p may serve as a clinical biomarker.

ORGANISM(S): Rattus

PROVIDER: GSE301484 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Vascular Calcification (VC) is a life threatening cardiovascular complication that accounts for high death rates particularly in association with diabetes, atherosclerosis and Chronic Kidney Disease (CKD. during VC, Vascular Smooth Muscle Cells (VSMCs) undergo reprogramming into osteoblast-like cells in response to calcium and phosphate mineral imbalance in CKD patients. This osteogenic switch is driven by the expression of several bone markers such as Runt- related transcription factor 2 (Runx2), Alkaline Phosphatase (ALP), Osteopontin (OPN), Matrix-Gla Protein (MGP), Osteocalcin (OCN), Type I Collagen (COL1), and Bone Sialo Proteins (BSPs). Recent studies showed that VSMCs secrete heterogeneous populations of Extracellular Vesicles (EVs)11 that are enriched under physiological conditions by calcification inhibitors such as Fetuin-A and MGP12,13,14. Interestingly, under pathological conditions, secreted EVs have a pro-calcifying profile and thereby act as nucleating foci for hydroxyapatite crystallization and propagation11,15. Electron Microscopy based studies revealed that EVs were embedded between collagen and elastin fibrils of arterial walls suggesting that calcification can be initiated through the EVs’ direct physical interaction with them13,16. We previously showed that a specific oligogalacturonic acid with a degree of polymerization of 8 (DP8) was able to inhibit vascular calcification. This inhibition was partly due to a decrease of osteogenic markers’s expression but also to the masking of a consensus sequence found in COL1 i.e. GFOGER sequence, thus preventing EVs from binding to COL1. Although the use of DP8 in-vivo seems to be compromised due to probable enzymatic digestion, these results suggested that the inhibition of VSMCs’ osteogenic switch and the prevention of EVs-COL1 interaction could represent new potential therapeutic targets for inhibiting VC17. Since we have already showed that the triple-helical GFOGER consensus sequence forms a preferential binding site for EVs17, we thereby chemically synthesized a GFOGER peptide in order to determine its ability to inhibit VC on VSMCs and on an aortic ring ex-vivo model. We also aim to decipher the mechanisms of inhibition by investigating the osteogenic markers’ expression as well as the protein content of secreted EVs in the presence of the GFOGER peptide.

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Dysfunctional Mesenchymal Stem Cell-derived Extracellular Vesicles in Chronic Kidney Disease: A Role in Vascular Calcification

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