Harnessing miRNA-Containing Extracellular Vesicles from Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Regeneration of Bone Defects: A Narrative Review of Mechanisms, Biomaterials, and Clinical Translation
Simple Summary
Abstract
1. Introduction
2. Methods
3. Characteristics, Mechanisms of Action, Effects, and Future Research Directions of MSC-Derived Exosomes in Bone Defects
3.1. Adipose-Derived Stem Cell Extracellular Vesicles (ADSC-EVs)
3.2. Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles (BMSC-EVs)
3.3. Dental Pulp Stem Cell-Derived Extracellular Vesicles (DPSC-EVs)
3.4. Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles (HucMSC-EVs)
3.5. Other EVs That May Be Involved in Bone Regeneration
3.6. Systemic and Cross-Organ Effects of EVs
4. EV-Encapsulated microRNAs Involved in Bone Regeneration and Their Mechanisms of Action
EV-Encapsulated microRNA | Mechanism of Action | EV Origin MSC/Source | Refs. |
---|---|---|---|
miR-148a-3p | Influences osteogenic differentiation and regulates osteoblast activity. Targets Smad ubiquitination regulatory factor 1 (SMURF1) in the SMAD signaling pathway, preventing the degradation of SMAD7. Promotes the expression of the anti-apoptotic protein BCL2, enhancing the viability and osteogenic potential of BMSCs. Promotes osteoblast differentiation by targeting specific genes involved in the osteogenic pathway. Enhances the expression of osteogenic markers, contributing to bone formation. | ADSCs BMSC-EVs ADSC-EVs | [31,36,38] |
let-7 g-5p | Involved in the regulation of osteogenic differentiation and apoptosis in osteoblasts | ADSCs | [36] |
let-7a | Involved in the regulation of osteogenic differentiation and matrix mineralization. | hASCs-EVs | [30,32,33] |
let-7i-5p | Promotes osteogenic differentiation of MSCs by targeting negative regulators of osteogenesis | ADSC-EVs | [31] |
miR-100 | Promotes osteogenic differentiation by enhancing the expression of osteogenic markers. | MSCs-EVs | [36] |
miR-100-5p | Involved in the regulation of signaling pathways that facilitate bone formation. | ADSCs | [33] |
miR-122-5p | Inhibits Sprouty2 (SPRY2), a receptor tyrosine kinase inhibitor in the MAPK pathway, thereby increasing MAPK pathway activity. Enhances the expression of RUNX2 and type I collagen (COL-I), promoting osteoblast proliferation | BMSC-EVs | [38] |
miR-148a | Influences osteogenic differentiation and regulates osteoblast activity, contributing to bone formation. | MSCs-EVs | [33] |
miR-151a-3p | Regulates osteoblast activity, enhancing their proliferation and function | ADSC-EVs | [31] |
miR-196a | Regulates osteoblastic differentiation and promotes the expression of osteogenic genes. | hBMSC-EVs | [30,32] |
miR-199b-5p | Enhances osteogenic differentiation and promotes bone regeneration by targeting specific genes involved in bone metabolism | BM-MSCs | [36] |
miR-200b | Influences osteogenic differentiation and may play a role in the regulation of signaling pathways involved in bone regeneration | BM-MSCs | [36] |
miR-206 | Enhances osteogenic differentiation and promotes the expression of key osteogenic markers. | hBMSC-EVs | [30,32] |
miR-21 | Enhances osteogenic differentiation and promotes bone healing by targeting genes involved in bone metabolism. Activates the PI3K/Akt signaling pathway, promoting cell survival and proliferation | MSCs-EVs HucMSCs-EVs | [31,33,38] |
miR-210 | Inhibits excessive activation of the PI3K/AKT/mTOR pathway, reducing endothelial cell apoptosis | BMSC-EVs | [38] |
miR-21-5p | Enhances osteogenic differentiation and promotes bone healing by targeting specific genes involved in bone metabolism | ADSCs | [36] |
miR-217 | Involved in the regulation of osteogenic differentiation and may influence the expression of osteogenic markers | BM-MSCs MSCs-EVs | [36] [33] |
miR-218 | Promotes bone regeneration by increasing the expression of osteogenic markers such as RUNX2 and ALP. | hASCs-EVs | [30,32] |
miR-22-3p | Inhibits the MYC/PI3K/AKT signaling pathway by targeting the fat mass and obesity-associated protein. | BM-MSCs | [30,35] |
miR-24 miR-24-3p | Regulates osteogenic differentiation and affects the expression of key osteogenic markers. | MSCs-EVs | [33,36] |
miR-26a | Enhances osteogenic differentiation and promotes bone formation by targeting specific genes. | BM-MSCs MSCs-EVs | [33,36] |
miR-27a | Promotes osteogenic differentiation and enhances bone regeneration by modulating target genes involved in bone metabolism. Promotes osteogenic differentiation and enhances the expression of osteogenic markers such as osteocalcin (OCN) and osteopontin (OPN). | hBMSC-EVs BM-MSCs | [30,32,33,36] |
miR-29b-3p | Promotes angiogenesis during fracture healing by being encapsulated in EVs and taken up by endothelial cells (e.g., HUVECs). Suppresses the expression of PTEN, a negative regulator of the PI3K/AKT signaling pathway, leading to enhanced cell proliferation and migration. | BM-MSCs | [30,34] |
miR-3084-3p | Upregulates RUNX2 and ALP, which are critical for osteogenic differentiation and matrix mineralization. Activates the Wnt/β-catenin signaling pathway, promoting bone formation. | BM-MSC-EVs | [32] |
miR-335 | Promotes osteogenic differentiation and enhances bone healing by modulating target genes involved in bone metabolism. Promotes osteoblast differentiation and bone fracture recovery by targeting VapB. Activates the Wnt/β-catenin signaling pathway, which is crucial for bone formation and repair. | MSCs-EVs BM-MSCs | [33,40] |
miR-335-5p | Promotes osteogenic differentiation and enhances bone healing by modulating target genes. | BM-MSCs | [36] |
miR-34a | Enhances bone regeneration by increasing the expression of RUNX2, ALP, and collagen type I (COL1A1). | hADSCs-EVs | [30,33] |
miR-375 | Improves osteogenic differentiation by inhibiting IGFBP3, which is involved in regulating growth factors. | hASCs-EVs | [30,33] |
miR-378 | Suppresses the expression of the Hh pathway inhibitor suppressor of fused homolog (Sufu), promoting the production of VEGF and angiopoietin-1 (ANG-1). | ADSCs | [38] |
miR-5100 | Contributes to the upregulation of osteogenic markers, promoting bone regeneration. | BM-MSC-EVs | [32] |
miR-677-3p | Involved in the regulation of osteogenic differentiation through the modulation of key osteogenic genes. | BM-MSC-EVs | [32] |
miR-680 | Contributes to the upregulation of RUNX2 and ALP, facilitating osteogenic differentiation. | BM-MSC-EVs | [32] |
miR-9 | Regulates osteogenic differentiation and may affect the expression of osteogenic markers. | BM-MSCs | [36] |
miR-92a | Involved in the regulation of osteogenic differentiation and may influence angiogenesis. | BM-MSCs | [36] |
5. Materials and Their Characteristics for EV Transport and Bone Regeneration
6. Challenges and Perspectives for Clinical Applications
7. Pro-Angiogenic and Immunomodulatory Properties
8. Conclusions and Future Direction
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
TLA | Three-letter acronyms |
MSC-EVs | Mesenchymal stromal cell-derived extracellular vesicles |
ADL | Activities of daily living |
mRNAs | Messenger RNAs |
BMPs | Bone morphogenetic proteins |
TME | Tumor microenvironment |
MSCs | Mesenchymal stromal cells |
EVs | Extracellular vesicles |
ADSC-EVs | Adipose-derived stem cell extracellular vesicles |
BMSC-EVs | Bone marrow-derived mesenchymal stromal cell extracellular vesicles |
USP7 | Ubiquitin-specific peptidase 7 |
DPSC-EVs | Dental pulp stem cell-derived extracellular vesicles |
ALP | Alkaline phosphatase |
OCN | Osteocalcin |
HucMSC-EVs | Human umbilical cord mesenchymal stem cell-derived extracellular vesicles |
MABs | Mesoangioblasts |
IdU | Idoxuridine |
Mu-EVs | Skeletal muscle secretes extracellular vesicles |
BMSCs | Bone marrow mesenchymal stem/stromal cells |
miR-208a | MicroRNA-208a |
SMURF1 | Smad ubiquitination regulatory factor 1 |
SPRY2 | Sprouty2 |
COL-I | Type I collagen |
OPN | Osteopontin |
Sufu | Suppressor of fused homolog |
ANG-1 | Angiopoietin-1 |
PLGA | Poly lactic-co-glycolic acid |
PEG | Polyethylene glycol |
(ISCT | International Society for Cellular Therapy |
DDS | Drug delivery systems |
OS | Osteosarcoma |
VEGF | Vascular endothelial growth factor |
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Material Type | (Sub Type) | Characteristics | Ref. |
---|---|---|---|
Biomaterial Scaffolds | Ceramic Scaffolds |
| [42] |
Polymer Scaffolds |
| [42] | |
Composite Scaffolds |
| [42] | |
Three-Dimensional Tissue Engineering Scaffolds | - |
| [41] |
Hydrogels | - |
| [42] |
Electrospun Nanofibers | - |
| [42] |
Bioactive Coatings | - |
| [42] |
Cationic Polymers | - |
| [43] |
Collagen Sponge | - |
| [43] |
β-TCP | - |
| [43] |
Biodegradable Polymers | PLGA PEG |
| [41] |
EV Origin | Advantages | Limitations | Potential Oncological Risks | Refs. |
---|---|---|---|---|
ADSC-EVs | Therapeutic Potential: Rich in bioactive molecules (proteins, lipids, RNAs, and microRNAs) that regulate inflammation, apoptosis, and tissue regeneration. Promote Healing: Enhance angiogenesis, cell survival, and accelerate wound healing, particularly in diabetic and osteoporotic models. Mechanisms of Action: Activate critical signaling pathways (e.g., PI3K/Akt and STAT3) essential for cell proliferation, migration, and differentiation. | Source Variability: The effects of ADSC-EVs can vary based on the tissue source of the MSCs, which may lead to inconsistent therapeutic outcomes. | Tumor Promotion: ADSC-EVs may promote glioma cell growth by enhancing the cell cycle and have been shown to increase OS cell growth, invasion, and migration, indicating a potential role in tumor progression. | [8,9,10,11,39,49] |
BMSC-EVs | Bone Regeneration: Significant potential in promoting bone regeneration and treating osteoporosis. Bioactive Content: Contain various bioactive molecules that facilitate intercellular communication and influence recipient cell behavior. Mechanistic Insights: Activate key signaling pathways (e.g., Wnt/β-catenin, BMP-2/Smad1/RUNX2) crucial for osteoblast differentiation and function. | Oncogenic Effects: BMSC-EVs can promote OS cell proliferation and migration through oncogenic pathways, indicating a dual role in both regeneration and tumor support. | Tumor Support: BMSC-EVs may enhance tumor growth and aggressiveness by transferring oncogenic factors and supporting autophagy in OS cells. | [14,15,39] |
DPSC-EVs | Osteogenic Potential: Promote osteogenic differentiation in MSCs and enhance the expression of osteogenic markers. Mechanistic Action: Activate the MAPK signaling pathway, particularly through ERK and JNK pathways, which are crucial for osteogenic effects. In Vivo Efficacy: Enhanced new bone formation in critical-sized defect models treated with DPSC-EVs. | Research Focus: Future research is needed to optimize therapeutic applications and identify specific proteins and microRNAs that contribute to their regenerative properties. | Limited Information: No explicit mention of oncological risks associated with DPSC-EVs, but caution is warranted given the potential for any stem cell-derived product to influence tumor behavior. | [3,19,20,49] |
HucMSC-EVs | Biocompatibility: High biocompatibility and low immunogenicity, making them suitable for therapeutic applications. Modulatory Effects: Enhance osteogenic differentiation and promote angiogenesis through critical signaling pathways (Wnt and Hippo). Immunomodulation: Polarize macrophages towards an anti-inflammatory phenotype, aiding tissue repair. | Optimization Needs: Current research trends focus on optimizing delivery systems and biomaterials to enhance bioavailability and efficacy. | Limited Evidence: No specific oncological risks for HucMSC-EVs, but their role in modulating immune responses could have implications for tumor interactions. | [22,23,49] |
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Goto, K.; Watanabe, D.; Yanagida, K.; Takagi, T.; Mizushima, A. Harnessing miRNA-Containing Extracellular Vesicles from Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Regeneration of Bone Defects: A Narrative Review of Mechanisms, Biomaterials, and Clinical Translation. Cancers 2025, 17, 2438. https://doi.org/10.3390/cancers17152438
Goto K, Watanabe D, Yanagida K, Takagi T, Mizushima A. Harnessing miRNA-Containing Extracellular Vesicles from Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Regeneration of Bone Defects: A Narrative Review of Mechanisms, Biomaterials, and Clinical Translation. Cancers. 2025; 17(15):2438. https://doi.org/10.3390/cancers17152438
Chicago/Turabian StyleGoto, Kashia, Daisuke Watanabe, Kazuki Yanagida, Tatsuya Takagi, and Akio Mizushima. 2025. "Harnessing miRNA-Containing Extracellular Vesicles from Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Regeneration of Bone Defects: A Narrative Review of Mechanisms, Biomaterials, and Clinical Translation" Cancers 17, no. 15: 2438. https://doi.org/10.3390/cancers17152438
APA StyleGoto, K., Watanabe, D., Yanagida, K., Takagi, T., & Mizushima, A. (2025). Harnessing miRNA-Containing Extracellular Vesicles from Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Regeneration of Bone Defects: A Narrative Review of Mechanisms, Biomaterials, and Clinical Translation. Cancers, 17(15), 2438. https://doi.org/10.3390/cancers17152438