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Cited by 69Extracellular vesicles in diseaseBone Tissue Engineering MaterialsMesenchymal stem cell research

Small extracellular vesicles released from bioglass/hydrogel scaffold promote vascularized bone regeneration by transferring miR-23a-3p

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Hu, Hongxing, Zhang, Hang, Bu, Ziheng, Liu, Zhongtang, Lv, Fang, Pan, Mingmang, Huang, Xuan, Cheng, Liming·2022·International Journal of Nanomedicine
DOI 10.2147/ijn.s389471PMC PMC9749034
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Abstract

Background: The treatment of critical-size bone defect is a great difficulty in orthopedics. Osteogenesis and angiogenesis are critical issue during the process of bone repair and remodeling. Mesenchymal stem cells (MSCs)-derived exosomes have the same therapeutic effect to MSCs-based therapies. The effect of human umbilical cord MSCs-derived sEVs (hUC-MSCs-sEVs) on vascularized bone regeneration and the potential mechanism remains to be investigated. Herein, we aimed to explore the therapeutic effect and the mechanism of hUC-MSCs-sEVs on critical-size bone defect. Methods: To investigate the potential osteogenesis and angiogenesis effects of sEVs in vitro, we extracted sEVs from hUC-MSCs, and then sEVs were co-incubated with BMSCs and HUVECs. We next investigated the effect and potential mechanism of sEVs on the effects of osteogenesis and angiogenesis. We fabricated 3D-printed bioglass scaffold with Gelma/nanoclay hydrogel coatings to load sEVs (BG-gel-sEVs) to ensure in vivo sustained efficacy of sEVs. Finally, the skull defect model was used to evaluate the capacity of vascularized bone regeneration of the composited scaffolds. Results: hUC-MSCs-sEVs facilitated calcium deposition and the endothelial network formation, inducing osteogenic differentiation and angiogenesis by delivering miR-23a-3p to activate PTEN/AKT signaling pathway. Additionally, the BG-gel-sEVs composited scaffold achieved vascularized bone regeneration in vivo. Conclusion: This finding illuminated that hUC-MSCs-sEVs promoted osteogenesis and angiogenesis by delivering miR-23a-3p to activate PTEN/AKT signaling pathway, achieving vascularized bone regeneration.

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  • During human cartilage regeneration, expression level of miR-23a-3p in small extracellular vesicles derived from umbilical cord mesenchymal stem cells was significantly ramped up, inhibiting PTEN.

    “during human cartilage regeneration, the expression level of miR-23a-3p in small extracellular vesicles derived from umbilical cord mesenchymal stem cells was significantly ramped up, inhibiting the expression level of PTEN.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [113]

    The Results section reports that hUC-MSC-derived sEVs significantly increased miR-23a-3p in recipient cells and decreased PTEN expression. The study examines osteogenesis and angiogenesis during bone regeneration, not an increase in vesicle miR-23a-3p during human cartilage regeneration. It mentions cartilage repair only as a finding of a previous study. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Human hemoglobin combined with vesicles-derived miR-23a-3p overexpression through gel scaffold can repair and reconstruct bone through the PTEN/AKT signal pathway, and promote osteogenesis and angiogenesis.

    “Human hemoglobin combined with vesicles-derived miR-23a-3p overexpression through gel scaffold can repair and reconstruct bone through PTEN/AKT signal pathway, and promote osteogenesis and angiogenesis [[111], [112], [113]].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [113]

    The Conclusions (page unavailable) report that small extracellular vesicles from human umbilical cord mesenchymal stem cells delivered miR-23a-3p, promoted osteogenesis and angiogenesis through PTEN/AKT signaling in vitro, and that a bioglass/hydrogel scaffold releasing the vesicles achieved vascularized bone regeneration. The source does not describe human hemoglobin as a component or establish that miR-23a-3p was overexpressed in the scaffold; its in vivo bone-repair finding and in vitro pathway finding are distinct. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Within the first 24 h of osteoclast formation, the miR-23 family displayed differential downregulation between undifferentiated cells and macrophages stimulated by RANKL.

    “Within the first 24 h of osteoclast formation, the miR-23 family displayed differential downregulation between undifferentiated cells and macrophages stimulated by receptor activator of nuclear factor-B ligand (RANKL).”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [113]

    The Results and Discussion discuss miR-23a-3p in bone marrow stromal and endothelial cells, including its increase after exposure to small extracellular vesicles. Searches for the first 24 hours of osteoclast formation and for RANKL-stimulated macrophages found no passage addressing the claimed miR-23-family downregulation. The reported increase concerns different cells and conditions, so it does not contradict the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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References 58 · Cited by 69

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Authors
Hu, H., Zhang, H., Bu, Z., Liu, Z., Lv, F., Pan, M., Huang, X., & Cheng, L.
Affiliations
  • Tongji University (CN)
  • Shanghai Jiao Tong University (CN)
  • Second Military Medical University (CN)
  • East China Normal University (CN)
Corresponding author
  • Huang, Xuan
  • Cheng, Liming
ORCID
Venue
International Journal of Nanomedicine
Publisher
Informa UK Limited
Published
2022-12
Volume
Volume 17
Pages
6201-6220
ISSN
  • 1176-9114 (ISSN-L)
  • 1178-2013
DOI
10.2147/ijn.s389471
PMC
PMC9749034
OpenAlex
W4311077829
Cited by
69
References
58
Citations by year
2026: 14 · 2025: 22 · 2024: 23 · 2023: 10
FWCI
4.49
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Nanomedicine (publishedVersion, cc-by-nc)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Funders
  • Natural Science Foundation of Shanghai
  • National Natural Science Foundation of China (51673212, 81802202, 81810001048, 82172437)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
small extracellular vesicles, human umbilical cord mesenchymal stem cells, miR-23a-3p, PTEN/AKT signaling pathway, bone formation, angiogenesis, vascularized bone regeneration, critical-size bone defect, 3D-printed scaffolds, exosome delivery
MeSH terms
Bone Regeneration, Ceramics, Humans, Osteogenesis, Hydrogels, MicroRNAs, Proto-Oncogene Proteins c-akt, Tissue Scaffolds, Exosomes

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