Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles

Ma, Cheng; Qi, Xin; Wei, Yifan; Li, Zhi; Zhang, Helong; Li, He; Yu, Fenglei; Pu, Yong; Huang, Yong‐Can; Ren, Yongxin

doi:10.1016/j.bioactmat.2022.03.042

Cited by 17 publications

(17 citation statements)

References 56 publications

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“…For example, Li P et al have demonstrated that miR-10396-3p is significantly decreased in the mechanical stress (MS)-induced HLF and overexpressing miR-10396-3p inhibits MS-induced HLF by targeting the inhibition expression of IL-11 [ 17 ]. Ma et al reported that delivering the two miRNAs (miR-146a-5p and miR-221-3p) to LF cells markedly suppressed fibrosis and hypertrophy of LF in vitro and vivo [ 20 ]. Our preliminary analysis found that miR-4306 has a potential binding site with TCF7 and negatively regulates TCF7 expression in HLF cells.…”

Section: Introductionmentioning

confidence: 99%

TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum

Duan

Qiu

et al. 2022

J Transl Med

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Background Hypertrophy of ligamentum flavum (HLF) is the mainly cause of lumbar spinal stenosis (LSS), but the precise mechanism of HLF formation has not been fully elucidated. Emerging evidence indicates that transcription factor 7 (TCF7) is the key downstream functional molecule of Wnt/β-catenin signaling, which participated in regulating multiple biological processes. However, the role and underlying mechanism of TCF7 in HLF is still unclear. Methods We used mRNAs sequencing analysis of human LF and subsequent confirmation with RT-qPCR, western blot and immunohistochemistry to identified the TCF7 in HLF tissues and cells. Then effect of TCF7 on HLF progression was investigated both in vitro and in vivo. Mechanically, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments were used to validate the regulation of TCF7/SNAI2/miR-4306 feedback loop. Results Our results identified for first time that the TCF7 expression was obviously elevated in HLF tissues and cells compared with control, and also found that TCF7 expression had significant positive correlation with LF thickness and fibrosis score. Notably, TCF7 inhibition suppressed the hyper-proliferation and fibrosis phenotype of HLF cells in vitro and ameliorated progression of HLF in mice in vivo, whereas TCF7 overexpression promoted hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Our data further revealed that TCF7 interacted with SNAI2 promoter to transactivated the SNAI2 expression, thereby promoting hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Furthermore, miR-4036 negatively regulated by SNAI2 could negatively feedback regulate TCF7 expression by directly binding to TCF7 mRNA 3’-UTR, thus inhibiting the hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Conclusions Our study demonstrated that TCF7 inhibition could suppress HLF formation by modulating TCF7/SNAI2/miR-4306 feedback loop, which might be considered as a novel potential therapeutic target for HLF.

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Section: Introductionmentioning

confidence: 99%

TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum

Duan

Qiu

et al. 2022

J Transl Med

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“…A recent study investigated Use of extracellular vesicles made from umbilical cord mesenchymal stromal cells to treat ligamentum flavum hypertrophy ( Ma et al, 2023 ). The macrophage migration inhibitory factor can be linked to LFH in type 2 diabetes ( Cisneros et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Immune cell infiltration and the genes associated with ligamentum flavum hypertrophy: Identification and validation

Duan

Zhao

et al. 2022

Front. Cell Dev. Biol.

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Ligamentum flavum hypertrophy (LFH) is a common cause of spinal stenosis. The aim of the current study was to identify the differentially expressed genes (DEGs) in LFH and the molecular mechanisms underlying the development of and immune responses to LFH. The gene expression omnibus (GEO) database was used to obtain the GSE113212 dataset, and the DEGs were derived from microarray data. To identify critical genes and signaling pathways, gene ontology enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network analyses were performed, followed by immune cell infiltration and Friends analyses using the retrieved datasets. The results were validated using quantitative real-time PCR. The 1530 DEGs identified comprised 971 upregulated and 559 downregulated genes. KEGG analysis revealed that DEGs were mostly enriched in the PI3K-Akt signaling pathway, while PPI network analysis identified tumor necrosis factor, interleukin (IL)-6, IL-10, epidermal growth factor receptor, and leptin as important nodes, which was validated by qPCR and IHC in human LFH tissues in vitro. A significant positive correlation was found between key LFH immune-related DEGs and several immune cell types, including T and B cells. The findings of the present study might lead to novel therapeutic targets and clinical approaches, as they provide insights into the molecular mechanisms of LFH.

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“…Since the CM was cleared of the lentiviral particles employed as editing vehicles, it was also depleted in extracellular vesicles (which are larger than 100 nm, similar to lentiviruses). 29 , 30 Moreover, treatment of the CM with RNase has not reduced the bystander effect, suggesting that is it mediated by proteins rather than RNA. Using MS analysis, we identified two new miR-10b targets, PGK1 and IGFBP2, whose expression and secretion from glioma cells were augmented by miR-10b ablation.…”

Section: Discussionmentioning

confidence: 99%