Single‐Cell Integration Analysis of Heterotopic Ossification and Fibrocartilage Developmental Lineage: Endoplasmic Reticulum Stress Effector Xbp1 Transcriptionally Regulates the Notch Signaling Pathway to Mediate Fibrocartilage Differentiation

Chen, Yisheng; Sun, Yaying; Xu, Yuzhen; Lin, Weiwei; Luo, Zhiwen; Han, Zhihua; Liu, Shaohua; Qi, Beijie; Sun, Chenyu; Go, Ken; Kang, Xueran; Chen, Jiwu

doi:10.1155/2021/7663366

Cited by 26 publications

(25 citation statements)

References 128 publications

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“…They exhibit stem cell properties, including a multidirectional differentiation potential, self-renewal ability, and clonogenicity [ 13 ]. TDSCs play a key role in tendon homeostasis and have been shown to promote the regeneration and repair of tendon injuries [ 14 , 15 ]. Among other factors, the correct differentiation and proliferation of TDSCs is key in tendon-to-bone healing [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

A Hyperglycemic Microenvironment Inhibits Tendon-to-Bone Healing through the let-7b-5p/CFTR Pathway

Cao

Hong

et al. 2022

Computational and Mathematical Methods in Medicine

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Background. Tendon-to-bone healing is a difficult process in treatment of rotator cuff tear (RCT). In addition, diabetes is an important risk factor for poor tendon-to-bone healing. Therefore, we investigated the specific mechanisms through which diabetes affects tendon-to-bone healing by regulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Methods. Tendon-derived stem cells (TDSCs) were extracted from rats after which their proliferative capacities were evaluated by the MTT assay. The expression levels of CFTR and tendon-related markers were determined by qRT-PCR. Then, bioinformatics analyses and dual luciferase reporter gene assays were used to identify miRNAs with the ability to bind CFTR mRNA. Finally, CFTR was overexpressed in TDSCs to validate the specific mechanisms through which the high glucose microenvironment inhibits tendon-to-bone healing. Results. The high glucose microenvironment downregulated mRNA expression levels of tendon-related markers and CFTR in TDSCs cultured with different glucose concentrations. Additionally, bioinformatics analyses revealed that let-7b-5p may be regulated by the high glucose microenvironment and can regulate CFTR levels. Moreover, a dual luciferase reporter gene assay was used to confirm that let-7b-5p targets and binds CFTR mRNA. Additional experiments also confirmed that overexpressed CFTR effectively reversed the negative effects of the hyperglycaemic microenvironment and upregulation of let-7b-5p on TDSC proliferation and differentiation. These findings imply that the hyperglycemic microenvironment inhibits CFTR transcription and, consequently, proliferation and differentiation of TDSCs in vitro by upregulating let-7b-5p. Conclusions. A hyperglycemic microenvironment inhibits TDSC proliferation in vitro via the let-7b-5p/CFTR pathway, and this is a potential mechanism in diabetes-induced poor tendon-to-bone healing.

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Section: Introductionmentioning

confidence: 99%

A Hyperglycemic Microenvironment Inhibits Tendon-to-Bone Healing through the let-7b-5p/CFTR Pathway

Cao

Hong

et al. 2022

Computational and Mathematical Methods in Medicine

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“…The log fold change (logFC) and mean expression values of all genes were also recorded. Adjusted p -values less than 0.05 were considered to be statistically significantly different ( Costa-Silva et al, 2017 ; Chen et al, 2021 ; Lin W. et al, 2021 ; Shi et al, 2021 ; Wu et al, 2021 ). The “pheatmap” package of the R software was used for heat m APP ing.…”

Section: Methodsmentioning

confidence: 99%

“…As previously described, scRNA analysis was performed using the Seurat package of R software, which included quality control, downscaling, and clustering of the GSE181279 dataset ( Chen et al, 2021 ; Lin W.-W. et al, 2021 ; Mangiola et al, 2021 ; Pereira et al, 2021 ; Shi et al, 2021 ; Wu et al, 2021 ). All genes were expressed in at least three cells.…”

Section: Methodsmentioning

confidence: 99%

Exercise Modifies the Transcriptional Regulatory Features of Monocytes in Alzheimer’s Patients: A Multi-Omics Integration Analysis Based on Single Cell Technology

Chen

Sun

Luo

et al. 2022

Front. Aging Neurosci.

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Monocytes have been reported to be important mediators of the protective effect of exercise against the development of Alzheimer’s disease (AD). This study aims explored the mechanism by which monocytes achieve this. Using single cell transcriptome analysis, results showed that CD14 + and CD16 + monocytes interacted with other cells in the circulating blood. TNF, CCR1, APP, and AREG, the key ligand-receptor-related genes, were found to be differentially expressed between exercise-treated and AD patients. The SCENIC analysis was performed to identify individual clusters of the key transcription factors (TFs). Nine clusters (M1-M9) were obtained from the co-expression network. Among the identified TFs, MAFB, HES4, and FOSL1 were found to be differentially expressed in AD. Moreover, the M4 cluster to which MAFB, HES4, and FOSL1 belonged was defined as the signature cluster for AD phenotype. Differential analysis by bulkRNA-seq revealed that the expression of TNF, CCR1, and APP were all upregulated after exercise (p < 0.05). And ATF3, MAFB, HES4, and KLF4 that were identified in M4 clusters may be the TFs that regulate TNF, CCR1, and APP in exercise prescription. After that, APP, CCR1, TNF, ATF3, KLF4, HES4, and MAFB formed a regulatory network in the ERADMT gene set, and all of them were mechanistically linked. The ERADMT gene set has been found to be a potential risk marker for the development of AD and can be used as an indicator of compliance to exercise therapy in AD patients. Using single-cell integration analysis, a network of exercise-regulating TFs in monocytes was constructed for AD disease. The constructed network reveals the mechanism by which exercise regulated monocytes to confer therapeutic benefits against AD and its complications. However, this study, as a bioinformatic research, requires further experimental validation.

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“…The cells isolated from mouse cerebrovascular tissue were clustered and annotated to facilitate subsequent analysis of transcriptional regulation patterns in different cell populations. Like previous research, the R package Seurat (v. 4.0) was used to perform quality control on the scRNA-seq data, as well as data reduction, cell clustering, and cell annotation ( 31 – 33 ). After identifying highly variable genes using the “FindVariableFeatures” function, the principal component analysis (PCA) was performed to extract gene expression features from scRNA-seq data.…”

Section: Methodsmentioning

confidence: 99%

hsa-miR-518-5p/hsa-miR-3135b Regulates the REL/SOD2 Pathway in Ischemic Cerebral Infarction

Zhao

Jiang

2022

Front. Neurol.

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ObjectivesIschemic cerebral infarction (ICI) is a fatal neurovascular disorder. A bioinformatics approach based on single-cell and bulk RNA-seq analyses was applied to investigate the pathways and genes involved in ICI and study the expression profile of these genes.MethodsFirst, the aberrantly regulated “small-molecule ribonucleic acids” [microRNA (miRNAs)] and messenger RNAs (mRNAs) were analyzed using transcriptome data from the ischemic brain infarction dataset of the Gene Expression Omnibus (GEO) database. In mouse cerebrovascular monocytes, the single-cell regulatory network inference and clustering (SCENIC) workflow was used to identify key transcription factors (TFs). Then, the two miRNA-TF-mRNA interaction networks were constructed. Moreover, the molecular complex detection (MCODE) extracted the core sub-networks and identified the important TFs within these sub-networks. Finally, whole blood samples were collected for validation of the expression of critical molecules in ICI.ResultsWe identified four cell types and 266 regulons in mouse cerebrovascular monocytes using SCENIC analysis. Moreover, 112 differently expressed miRNAs and 3,780 differentially expressed mRNAs were identified. We discovered potential biomarkers in ICI by building a miRNA-TF-mRNA interaction network. The hsa-miR-518-5p/hsa-miR-3135b/REL/SOD2 was found to play a potential role in ICI progression. The expression of REL and superoxide dismutase 2 (SOD2) was significantly elevated in the ICI group in the clinical cohort (P < 0.05). Furthermore, a REL expression was elevated in endothelial cells and fibroblasts at the single-cell level, indicating that REL is a cell-specific regulon. Functional enrichment analyses revealed that REL is primarily engaged in neurotransmitter activity and oxidative phosphorylation.ConclusionsOur research uncovered novel biomarkers for ICI of neurovascular disease. The hsa-miR-518-5p/hsa-miR-3135b may regulate the REL/SOD2 pathway in ICI progression.

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Single‐Cell Integration Analysis of Heterotopic Ossification and Fibrocartilage Developmental Lineage: Endoplasmic Reticulum Stress Effector Xbp1 Transcriptionally Regulates the Notch Signaling Pathway to Mediate Fibrocartilage Differentiation

Cited by 26 publications

References 128 publications

A Hyperglycemic Microenvironment Inhibits Tendon-to-Bone Healing through the let-7b-5p/CFTR Pathway

A Hyperglycemic Microenvironment Inhibits Tendon-to-Bone Healing through the let-7b-5p/CFTR Pathway

Exercise Modifies the Transcriptional Regulatory Features of Monocytes in Alzheimer’s Patients: A Multi-Omics Integration Analysis Based on Single Cell Technology

hsa-miR-518-5p/hsa-miR-3135b Regulates the REL/SOD2 Pathway in Ischemic Cerebral Infarction

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