Key Takeaways & Executive Findings
- •• BMSC-EVs attenuate vascular calcification in type 2 diabetes by inhibiting endothelial-to-mesenchymal transition and ferroptosis. • miR-32 deficiency in BMSC-EVs enhances their protective effect against vascular calcification. • The protective mechanism involves regulation of the MAPK/FoxO signaling pathway. • BMSC-EVs represent a promising cell-free therapeutic strategy for diabetic vascular calcification.
Abstract
Background The development of vascular calcification (VC) in diabetes is closely related to the endothelial-to-mesenchymal transition (EndMT). We found that microRNA-32-5p (miR-32) was elevated in the plasma of calcification patients. However, it is unclear whether miR-32 mediates the function of bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) in type 2 diabetes (T2D) VC. Methods BMSC-EVs were characterized by TEM, NTA, Western blotting, and confocal microscopy. Alizarin Red and ALP staining assessed the severity of VC. qRT-PCR and Western blotting evaluated the expression of BMP2, RUNX2, GPX4, SLC7A11, VE-cadherin, and N-cadherin, while immunofluorescence was used for detecting VE-cadherin and N-cadherin. In vivo validation was performed using miR-32–/– and ApoE–/– mice. RNA sequencing (RNA-seq) and bioinformatics analysis was conducted to explore underlying mechanisms. Results We demonstrated that BMSC-EVs attenuate VC in endothelial cells (ECs) and inhibit EndMT. In vivo, histological analysis showed that treatment with BMSC-EVs significantly reduced the severity of VC associated with T2D. Notably, knockout of miR-32 further enhanced the inhibitory effect of BMSC-EVs on VC. Mechanistically, transcriptomic and functional analyses suggest that the protective effect of BMSC-EVs on VC is associated with regulation of the MAPK/FoxO signaling pathway, potentially mediated by modulation of ferroptosis. Conclusion These findings demonstrate that BMSC-EVs attenuate T2D-associated VC, partially through miR-32-mediated suppression of EC ferroptosis.
1. Introduction
Vascular calcification (VC), characterized by abnormal mineral deposition in blood vessels, is prevalent in type 2 diabetes (T2D) patients [1, 2]. This process is considered an active and potentially modifiable physiological event. Depending on location, VC can affect the intima, media, valves, or other tissues, with T2D-associated VC primarily involving the intima and media [3, 4]. VC increases vascular stiffness and reduces compliance, leading to elevated pulse pressure, ventricular hypertrophy, altered left ventricular pressure, and changes in coronary artery diameter [5]. Studies have shown that cardiovascular disease is strongly associated with increased mortality from T2D, particularly VC [6, 7]. While some drugs and surgical interventions can mitigate VC progression, effective treatments remain lacking [8]. Addressing VC is crucial for reducing cardiovascular complications and improving T2D prognosis. Therefore, the development of novel and effective therapeutic strategies for VC is urgently needed.
Endothelial-to-mesenchymal transition (EndMT) is a hallmark of VC [9]. During EndMT, endothelial cells (ECs) begin to express markers typically associated with vascular smooth muscle cells (VSMCs) or mesenchymal stem cell-like phenotypes, such as α-SMA, SM22α, VE-cadherin, and N-cadherin [10]. This process can initially help maintain indicators of lesion stability; however, this temporary protective effect diminishes as the condition progresses to more advanced stages [11]. EndMT has also been implicated in various cardiovascular and metabolic diseases, including VC, obesity, hypertension, hyperlipidemia, and T2D. As such, it is increasingly recognized as a potential therapeutic target for vascular diseases.
The therapeutic potential of BMSCs has garnered significant attention in recent years, particularly with respect to the extracellular vesicles they secrete [12]. Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are rich in bioactive substances, including proteins, RNA (miRNA, lncRNA, and mRNA), and lipids, which play vital roles in tissue repair, inflammation regulation, cellular metabolism, and various forms of cell death [13, 14]. As a novel cell-free therapeutic strategy, EVs-based therapy provides a promising alternative for injection-based treatment approaches. Accumulating evidence supports the therapeuti
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Zhengjie Lin, Anqi Li, Jie Zheng, Kun Luo, Fei Liang, Shiyan Liu, Zhengfeng Liang, Wei Liu, Jian Tang, Xiaolin Zhong, Jianghua Liu (2026). Deficiency of extracellular vesicles miR-32 from bone marrow mesenchymal stem cells alleviates vascular calcification in type 2 diabetes by inhibiting endothelial ferroptosis. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-04896-8
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Frequently Asked Questions
What is the role of miR-32 in vascular calcification?
The study found that miR-32 is elevated in plasma of calcification patients and its deficiency in BMSC-EVs enhances their protective effect against vascular calcification, suggesting that miR-32 promotes calcification.
How do BMSC-EVs alleviate vascular calcification?
BMSC-EVs attenuate vascular calcification by inhibiting endothelial-to-mesenchymal transition and ferroptosis, partly through regulation of the MAPK/FoxO signaling pathway.
What is the significance of this study for diabetes treatment?
The findings suggest that BMSC-EVs, particularly those with miR-32 deficiency, could be a promising cell-free therapeutic strategy for diabetic vascular calcification, potentially improving cardiovascular outcomes in T2D patients.
What experimental models were used?
The study used in vitro endothelial cell models and in vivo miR-32 knockout and ApoE knockout mice to validate the effects of BMSC-EVs on vascular calcification.
What is the underlying mechanism of BMSC-EVs' protective effect?
The protective effect is associated with regulation of the MAPK/FoxO signaling pathway, potentially mediated by modulation of ferroptosis, a form of regulated cell death.
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