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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.
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Oxidative medicine and cellular longevity [Oxid Med Cell Longev] 2021 Oct 26; Vol. 2021, pp. 7663366. Date of Electronic Publication: 2021 Oct 26 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- Introduction: Regeneration of fibrochondrocytes is essential for the healing of the tendon-bone interface (TBI), which is similar to the formation of neurogenic heterotopic ossification (HO). Through single-cell integrative analysis, this study explored the homogeneity of HO cells and fibrochondrocytes.<br />Methods: This study integrated six datasets, namely, GSE94683, GSE144306, GSE168153, GSE138515, GSE102929, and GSE110993. The differentiation trajectory and key transcription factors (TFs) for HO occurrence were systematically analyzed by integrating single-cell RNA (scRNA) sequencing, bulk RNA sequencing, and assay of transposase accessible chromatin seq. The differential expression and enrichment pathways of TFs in heterotopically ossified tissues were identified.<br />Results: HO that mimicked pathological cells was classified into HO1 and HO2 cell subsets. Results of the pseudo-temporal sequence analysis suggested that HO2 is a differentiated precursor cell of HO1. The analysis of integrated scRNA data revealed that ectopically ossified cells have similar transcriptional characteristics to cells in the fibrocartilaginous zone of tendons. The modified SCENIC method was used to identify specific transcriptional regulators associated with ectopic ossification. Xbp1 was defined as a common key transcriptional regulator of ectopically ossified tissues and the fibrocartilaginous zone of tendons. Subsequently, the CellPhoneDB database was completed for the cellular ligand-receptor analysis. With further pathway screening, this study is the first to propose that Xbp1 may upregulate the Notch signaling pathway through Jag1 transcription. Twenty-four microRNAs were screened and were found to be potentially associated with upregulation of XBP1 expression after acute ischemic stroke.<br />Conclusion: A systematic analysis of the differentiation landscape and cellular homogeneity facilitated a molecular understanding of the phenotypic similarities between cells in the fibrocartilaginous region of tendon and HO cells. Furthermore, by identifying Xbp1 as a hub regulator and by conducting a ligand-receptor analysis, we propose a potential Xbp1/Jag1/Notch signaling pathway.<br />Competing Interests: The authors declare no conflict of interest.<br /> (Copyright © 2021 Yisheng Chen et al.)
- Subjects :
- Animals
Bone and Bones metabolism
Cell Differentiation
Cell Lineage
Fibrocartilage metabolism
Gene Expression Profiling
Humans
Male
Mice, Inbred C57BL
Ossification, Heterotopic genetics
Ossification, Heterotopic metabolism
Osteogenesis
Receptors, Notch genetics
X-Box Binding Protein 1 genetics
Mice
Bone and Bones pathology
Endoplasmic Reticulum Stress
Fibrocartilage pathology
Ossification, Heterotopic pathology
Receptors, Notch metabolism
Single-Cell Analysis methods
X-Box Binding Protein 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1942-0994
- Volume :
- 2021
- Database :
- MEDLINE
- Journal :
- Oxidative medicine and cellular longevity
- Publication Type :
- Academic Journal
- Accession number :
- 34737845
- Full Text :
- https://doi.org/10.1155/2021/7663366