SHED aggregate exosomes shuttled miR‐26a promote angiogenesis in pulp regeneration via TGF‐β/SMAD2/3 signalling

Xuan, Kun; Liu, Xuemei; Li, Zihan; Huang, Xiaoguang; Guo, Hao; Guo, Xiang; Yang, Xiaoxue; Li, Bei; Xuan, Kun; Jin, Yan

doi:10.1111/cpr.13074

Cited by 69 publications

(71 citation statements)

References 55 publications

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“…During the preparation of our manuscript, we found a very recent study, which reported that exosomes derived from SHED aggregates actually enhanced angiogenesis through shuttling miR-26a [ 48 ], which is contrary to our finding. After carefully studying the report from Wu et al, we found that the main differences between our study and theirs are the culture methods and the conditions used to prepare SHED-Exos.…”

Section: Discussioncontrasting

confidence: 99%

Exosomes derived from stem cells of human deciduous exfoliated teeth inhibit angiogenesis in vivo and in vitro via the transfer of miR-100-5p and miR-1246

Zhang

et al. 2022

Stem Cell Res Ther

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Background Anti-angiogenic therapy has been shown to be a promising strategy for anti-tumor treatment. Increasing evidence indicates that tumor angiogenesis is affected by exosomes that are secreted by mesenchymal stem cells (MSCs), but whether exosomes derived from MSCs suppress or promote angiogenesis remain paradoxical. The purpose of this study focused on understanding the potential role of exosomes derived from stem cells of human deciduous exfoliated teeth (SHED-Exos) in regulating angiogenesis and the underlying molecular mechanism. Methods Exosomes were isolated from supernatants of SHED cells using an exosome purification kit and were characterized by transmission electron microscopy, nanoparticle tracking analysis and western blot analysis. Cell Counting Kit-8, flow cytometric assays, western blots, wound healing and transwell migration assays were performed to characterize the roles of SHED-Exos on cell proliferation, apoptosis and migration of human umbilical vein endothelial cells (HUVECs). The anti-angiogenic activity of SHED-Exos was assessed via a tube formation assay of endothelial cells and angiogenesis-related factors were analyzed by western blotting. In vivo, we used the chick chorioallantoic membrane (CAM) assay and an oral squamous cell carcinoma (OSCC) xenograft transplantation model with nude mice that received multi-point injections at three-day intervals to evaluate the effects on angiogenesis. Furthermore, the sequencing of microRNAs (miRNAs) in SHED-Exos was performed to investigate the underlying anti-angiogenic mechanism. Results The results showed that SHED-Exos inhibit cell proliferation and migration and induce apoptosis in HUVECs. SHED-Exos suppress the tube-like structure formation of HUVECs in vitro. SHED-Exos downregulate several angiogenesis-related factors, including VEGFA, MMP-9 and ANGPT1. In vivo, the chick CAM assay verified that treatment with SHED-Exos inhibits micro-vascular formation, and importantly, significantly reduces the micro-vascular formation of tumors generated from xenografted OSCC cells, which was associated with the inhibition of tumor growth in vivo. Mechanistically, our data suggested that SHED-Exos are enriched with miR-100-5p and miR-1246 and are transferred to endothelial cells, which results in decreased tube formation via the down-regulation of VEGFA expression. Conclusions These results demonstrate that SHED-Exos inhibit angiogenesis in vitro and in vivo, which suggests that SHED-Exos could potentially serve as a novel and effective therapeutic approach for anti-angiogenic treatment.

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Section: Discussioncontrasting

confidence: 99%

Exosomes derived from stem cells of human deciduous exfoliated teeth inhibit angiogenesis in vivo and in vitro via the transfer of miR-100-5p and miR-1246

Zhang

et al. 2022

Stem Cell Res Ther

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“…It has been also reported that exosomes extracted from dental pulp stem cells (DPSCs) could promote the osteogenic differentiation of BMSCs, and had strong potential in facilitating pulp regeneration in animal model (41). Other group showed exosomes came from deciduous teeth (SHED) could promote angiogenesis of human umbilical vascular endothelial cells (hUVECs) and angiogenesis in vivo (42). With the continuous deepening of basic research, it is expected that sEVs will be introduced into the clinic in the future and applied in the field of craniofacial bone defect restoration (43).…”

Section: Discussionmentioning

confidence: 99%

Osteogenically Induced Human Umbilical Cord Mesenchymal Stem Cell-derived Small Extracellular Vesicles Carrying Distinct microRNA Signature Improve Osteoinductivity of Tissue-engineered Bone

Zhou

Rong

et al. 2022

Preprint

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Background: Clinical application of stem cell-based tissue-engineered bone (TEB) has been severely hindered by a low viability of seed cells, slow osteogenesis and biosafety. Mesenchymal stem cells-derived small extracellular vesicles (sEVs) possess similar properties to donor cells and have low immunogenicity, strong stability and favorable biosafety. It’s validated that human umbilical cord mesenchymal stem cells-derived sEVs (hUCMSCs-sEVs) exert therapeutic effects on various diseases. However, little is known whether hUCMSCs-sEVs can effectively be used to construct TEB. This study aimed to investigate whether hUCMSCs-sEVs bore positive effects on bone regeneration and elucidate the underlying mechanisms. Methods: Herein, PM-sEVs and OM-sEVs were separately harvested from proliferation medium (PM) and osteogenic medium (OM) cultured hUCMSCs and identified. The effects of PM-sEVs and OM-sEVs on the bioactivities and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) were evaluated. The differential microRNAs (miRNAs) expressions between PM-sEVs and OM-sEVs were screened by miRNA sequencing. Furthermore, PM-sEVs and OM-sEVs were separately incorporated in tricalcium phosphate (TCP) scaffolds to build TEBs, which were used to repair critical-sized calvarial bone defects of rats. Results: Both PM-sEVs and OM-sEVs had similar morphology, size and expressed specific surface markers of exosomes while didn’t have the surface marker from donor cells. Both PM-sEVs and OM-sEVs could be internalized by hBMSCs, thus significantly promoting the migration, proliferation and osteogenic differentiation of hBMSCs. Remarkably, OM-sEVs outweighed PM-sEVs in accelerating hBMSCs’ migration and osteogenic differentiation. Besides, miRNA sequencing analysis revealed that several differentially expressed miRNAs might be responsible for sEVs’ bioactivities. Furthermore, OM-sEVs could sustainably release from TCP scaffolds, and the resultant TEB had better reparative outcome than that of PM-sEVs group and pure TCP. Conclusion: sEVs isolated from osteogenically induced hUCMSCs (OM-sEVs) could prominently facilitate osteogenic differentiation of hBMSCs by unique miRNAs signature. TEB graft derived from OM-sEVs provided a promising alternative for clinical transplantation.

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“…In the recipient endothelial cells, DSC-EVs and their delivered miR-26a may function through regulating the angiogenic TGF-β/SMAD2/3 pathway. 34 Of interest, researchers have also indicated that bone marrow mesenchymal stem cell-derived EVs (BMMSC-EVs) possess pro-angiogenic effects, but they may function through miR-21 and miR-1246, being different from DSC-EVs. 35 …”

Section: Dsc-evs As Potential Saviors For the Treatment Of Diseasesmentioning

confidence: 99%

Dental stem cell-derived extracellular vesicles as promising therapeutic agents in the treatment of diseases

Duan

Chen

et al. 2022

Int J Oral Sci

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Dental stem cells (DSCs), an important source of mesenchymal stem cells (MSCs), can be easily obtained by minimally invasive procedures and have been used for the treatment of various diseases. Classic paradigm attributed the mechanism of their therapeutic action to direct cell differentiation after targeted migration, while contemporary insights into indirect paracrine effect opened new avenues for the mystery of their actual low engraftment and differentiation ability in vivo. As critical paracrine effectors, DSC-derived extracellular vesicles (DSC-EVs) are being increasingly linked to the positive effects of DSCs by an evolving body of in vivo studies. Carrying bioactive contents and presenting therapeutic potential in certain diseases, DSC-EVs have been introduced as promising treatments. Here, we systematically review the latest in vivo evidence that supports the therapeutic effects of DSC-EVs with mechanistic studies. In addition, current challenges and future directions for the clinical translation of DSC-EVs are also highlighted to call for more attentions to the (I) distinguishing features of DSC-EVs compared with other types of MSC-EVs, (II) heterogeneity among different subtypes of DSC-derived EVs, (III) action modes of DSC-EVs, (IV) standardization for eligible DSC-EVs and (V) safety guarantee for the clinical application of DSC-EVs. The present review would provide valuable insights into the emerging opportunities of DSC-EVs in future clinical applications.

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SHED aggregate exosomes shuttled miR‐26a promote angiogenesis in pulp regeneration via TGF‐β/SMAD2/3 signalling

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 69 publications

References 55 publications

Exosomes derived from stem cells of human deciduous exfoliated teeth inhibit angiogenesis in vivo and in vitro via the transfer of miR-100-5p and miR-1246

Exosomes derived from stem cells of human deciduous exfoliated teeth inhibit angiogenesis in vivo and in vitro via the transfer of miR-100-5p and miR-1246

Osteogenically Induced Human Umbilical Cord Mesenchymal Stem Cell-derived Small Extracellular Vesicles Carrying Distinct microRNA Signature Improve Osteoinductivity of Tissue-engineered Bone

Dental stem cell-derived extracellular vesicles as promising therapeutic agents in the treatment of diseases

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