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基于微小RNA的间充质干细胞外泌体工程:靶向骨形态发生蛋白2级联反应促进骨修复

Micro RNA based MSC EV engineering: Targeting the BMP2 cascade for bone repair.

作者信息

Huang Chun-Chieh, Kang Miya, Leung Kasey, Lu Yu, Shirazi Sajjad, Gajendrareddy Praveen, Ravindran Sriram

机构信息

Department of Oral Biology, University of Illinois Chicago, Chicago, Illinois, United States.

Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, Illinois, United States.

出版信息

Front Cell Dev Biol. 2023 Feb 8;11:1127594. doi: 10.3389/fcell.2023.1127594. eCollection 2023.


DOI:10.3389/fcell.2023.1127594
PMID:36846585
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9945088/
Abstract

Mesenchymal stem cell derived extracellular vesicles (MSC EVs) possess excellent immunomodulatory and therapeutic properties. While beneficial, from a translational perspective, extracellular vesicles with consistent functionality and target specificity are required to achieve the goals of precision medicine and tissue engineering. Prior research has identified that the miRNA composition of mesenchymal stem cell derived extracellular vesicles contributes significantly towards extracellular vesicles functionality. In this study, we hypothesized that mesenchymal stem cell derived extracellular vesicle functionality can be rendered pathway-specific using a miRNA-based extracellular vesicles engineering approach. To test this hypothesis, we utilized bone repair as a model system and the BMP2 signaling cascade as the targeted pathway. We engineered mesenchymal stem cell extracellular vesicles to possess increased levels of miR-424, a potentiator of the BMP2 signaling cascade. We evaluated the physical and functional characteristics of these extracellular vesicles and their enhanced ability to trigger the osteogenic differentiation of naïve mesenchymal stem cell and facilitate bone repair Results indicated that the engineered extracellular vesicles retained their extracellular vesicles characteristics and endocytic functionality and demonstrated enhanced osteoinductive function by activating SMAD1/5/8 phosphorylation and mesenchymal stem cell differentiation and enhanced bone repair Furthermore, the inherent immunomodulatory properties of the mesenchymal stem cell derived extracellular vesicles remained unaltered. These results serve as a proof-of-concept for miRNA-based extracellular vesicles engineering approaches for regenerative medicine applications.

摘要

间充质干细胞衍生的细胞外囊泡(MSC EVs)具有出色的免疫调节和治疗特性。虽然有益,但从转化医学的角度来看,需要具有一致功能和靶标特异性的细胞外囊泡来实现精准医学和组织工程的目标。先前的研究已经确定,间充质干细胞衍生的细胞外囊泡的miRNA组成对细胞外囊泡的功能有显著贡献。在本研究中,我们假设可以使用基于miRNA的细胞外囊泡工程方法使间充质干细胞衍生的细胞外囊泡功能具有途径特异性。为了验证这一假设,我们将骨修复作为模型系统,将BMP2信号级联作为靶向途径。我们对间充质干细胞外囊泡进行工程改造,使其具有更高水平的miR-424,miR-424是BMP2信号级联的增强剂。我们评估了这些细胞外囊泡的物理和功能特性,以及它们触发未处理的间充质干细胞成骨分化和促进骨修复的增强能力。结果表明,工程化的细胞外囊泡保留了其细胞外囊泡特征和内吞功能,并通过激活SMAD1/5/8磷酸化和间充质干细胞分化表现出增强的骨诱导功能以及增强的骨修复能力。此外,间充质干细胞衍生的细胞外囊泡固有的免疫调节特性保持不变。这些结果为基于miRNA的细胞外囊泡工程方法在再生医学应用中提供了概念验证。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/bd4bbc2d1f10/fcell-11-1127594-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/cc9bb0adc617/fcell-11-1127594-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/545703361327/fcell-11-1127594-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/1b5f7fc116de/fcell-11-1127594-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/217808ec33f1/fcell-11-1127594-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/3f7e9ec1691f/fcell-11-1127594-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/03df203f3055/fcell-11-1127594-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/38ccec61944d/fcell-11-1127594-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/bd4bbc2d1f10/fcell-11-1127594-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/cc9bb0adc617/fcell-11-1127594-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/545703361327/fcell-11-1127594-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/1b5f7fc116de/fcell-11-1127594-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/217808ec33f1/fcell-11-1127594-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/3f7e9ec1691f/fcell-11-1127594-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/03df203f3055/fcell-11-1127594-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/38ccec61944d/fcell-11-1127594-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a600/9945088/bd4bbc2d1f10/fcell-11-1127594-g008.jpg

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引用本文的文献

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Mesenchymal stem cells: A new strategy for the treatment of femoral head necrosis.

Regen Ther. 2025-7-23

[2]
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[5]
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[6]
Mesenchymal stem cell-derived extracellular vesicles in periodontal bone repair.

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[7]
Critical roles of extracellular vesicles in periodontal disease and regeneration.

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[8]
Functionality of lyophilized osteoinductive EVs: a mechanistic study.

Front Bioeng Biotechnol. 2024-10-22

[9]
Immunomodulatory properties of naïve and inflammation-informed dental pulp stem cell derived extracellular vesicles.

Front Immunol. 2024

[10]
MicroRNA-based engineered mesenchymal stem cell extracellular vesicles to treat visual deficits after blast-induced trauma.

Exp Eye Res. 2024-10

本文引用的文献

[1]
MicroRNA-based engineering of mesenchymal stem cell extracellular vesicles for treatment of retinal ischemic disorders: Engineered extracellular vesiclesand retinal ischemia.

Acta Biomater. 2023-3-1

[2]
Bioscreening and pre-clinical evaluation of the impact of bioactive molecules from Ptychotis verticillata on the multilineage potential of mesenchymal stromal cells towards immune- and inflammation-mediated diseases.

Inflamm Res. 2022-8

[3]
Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration.

Front Immunol. 2022

[4]
miR-424 inhibits apoptosis and inflammatory responses induced by sevoflurane through TLR4/MyD88/NF-κB pathway.

BMC Anesthesiol. 2022-2-23

[5]
An overview of mesenchymal stem cells and their potential therapeutic benefits in cancer therapy.

Oncol Lett. 2021-11

[6]
The miR-424(322)/503 gene cluster regulates pro- versus anti-inflammatory skin DC subset differentiation by modulating TGF-β signaling.

Cell Rep. 2021-4-27

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Therapeutic potential of mesenchymal stem cells in multiple organs affected by COVID-19.

Life Sci. 2021-8-1

[8]
3D Encapsulation and tethering of functionally engineered extracellular vesicles to hydrogels.

Acta Biomater. 2021-5

[9]
The importance of cellular and exosomal miRNAs in mesenchymal stem cell osteoblastic differentiation.

Sci Rep. 2021-3-15

[10]
Macrophage Control of Incipient Bone Formation in Diabetic Mice.

Front Cell Dev Biol. 2021-1-25

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