Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment

Arthur, Agnieszka; Gronthos, Stan

doi:10.3389/fcell.2021.598612

Cited by 29 publications

(18 citation statements)

References 187 publications

(116 reference statements)

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“…This effect could be through both direct effects on osteoblast precursors and indirect effects via consuming the osteogenic lineage by enhancing fibrosis. Therefore, since the Eph receptors are potential therapeutic targets for multiple clinical conditions 90 , 100 - 103 , we speculate that the inhibition of Ephrin-Eph signaling may facilitate clinical bone defect healing after initial periodontal therapy.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA landscape of the osteoimmunology microenvironment in periodontitis

Chen¹,

Wang²,

Yang³

et al. 2022

Theranostics

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Single-cell RNA sequencing (scRNA-seq) enables specific profiling of cell populations at single-cell resolution. The osteoimmunology microenvironment in the occurrence and development of periodontitis remains poorly understood at the single-cell level. In this study, we used single-cell transcriptomics to comprehensively reveal the complexities of the molecular components and differences with counterparts residing in periodontal tissues. Methods: We performed scRNA-seq to identify 51248 single cells from healthy controls (n=4), patients with severe chronic periodontitis (n=5), and patients with severe chronic periodontitis after initial periodontal therapy within 1 month (n=3). Uniform manifold approximation and projection (UMAP) were further conducted to explore the cellular composition of periodontal tissues. Pseudotime cell trajectory and RNA velocity analysis, combined with gene enrichment analysis were used to reveal the molecular pathways underlying cell fate decisions. CellPhoneDB were performed to identify ligand-receptor pairs among the major cell types in the osteoimmunology microenvironment of periodontal tissues. Results: A cell atlas of the osteoimmunology microenvironment in periodontal tissues was characterized and included ten major cell types, such as fibroblasts, monocytic cells, endothelial cells, and T and B cells. The enrichment of TNFRSF21 + fibroblasts with high expression of CXCL1, CXCL2, CXCL5, CXCL6, CXCL13 , and IL24 was detected in patients with periodontitis compared to healthy individuals. The fractions of CD55 + mesenchymal stem cells (MSCs), APOE + pre-osteoblasts (pre-OBs), and IBSP + osteoblasts decreased significantly in response to initial periodontal therapy. In addition, CXCL12 + MSC-like pericytes could convert their identity into a pre-OB state during inflammatory responses even after initial periodontal therapy confirmed by single-cell trajectory. Moreover, we portrayed the distinct subtypes of monocytic cells and abundant endothelial cells significantly involved in the immune response. The heterogeneity of T and B cells in periodontal tissues was characterized. Finally, we mapped osteoblast/osteoclast differentiation mediators to their source cell populations by identifying ligand-receptor pairs and highlighted the effects of Ephrin-Eph signaling on bone regeneration after initial periodontal therapy. Conclusions: Our analyses uncovered striking spatiotemporal dynamics in gene expression, population composition, and cell-cell interactions during periodontitis progression. These findings provide insights into the cellular and molecular underpinning of periodontal bone regeneration.

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Section: Discussionmentioning

confidence: 99%

Single-cell RNA landscape of the osteoimmunology microenvironment in periodontitis

Chen¹,

Wang²,

Yang³

et al. 2022

Theranostics

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“…Thus, these well-characterized osteoblastic proteins [ 20 , 21 , 22 , 28 , 29 , 30 ]) should not only be regarded as single molecules but as parts of a complex osteoblast-specific protein interaction network.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Comparison of Bone Marrow Derived Osteoblasts and Mesenchymal Stem Cells

Aasebø

Brenner

Hernandez-Valladares

et al. 2021

IJMS

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Mesenchymal stem cells (MSCs) can differentiate into osteoblasts, and therapeutic targeting of these cells is considered both for malignant and non-malignant diseases. We analyzed global proteomic profiles for osteoblasts derived from ten and MSCs from six healthy individuals, and we quantified 5465 proteins for the osteoblasts and 5420 proteins for the MSCs. There was a large overlap in the profiles for the two cell types; 156 proteins were quantified only in osteoblasts and 111 proteins only for the MSCs. The osteoblast-specific proteins included several extracellular matrix proteins and a network including 27 proteins that influence intracellular signaling (Wnt/Notch/Bone morphogenic protein pathways) and bone mineralization. The osteoblasts and MSCs showed only minor age- and sex-dependent proteomic differences. Finally, the osteoblast and MSC proteomic profiles were altered by ex vivo culture in serum-free media. We conclude that although the proteomic profiles of osteoblasts and MSCs show many similarities, we identified several osteoblast-specific extracellular matrix proteins and an osteoblast-specific intracellular signaling network. Therapeutic targeting of these proteins will possibly have minor effects on MSCs. Furthermore, the use of ex vivo cultured osteoblasts/MSCs in clinical medicine will require careful standardization of the ex vivo handling of the cells.

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“…The most recurrent core signaling pathway in our panel was Eph-ephrin (Figure 5B, rightmost blue point), another juxtacrine signaling pathway that plays key roles in development, including tissue boundary formation, axon guidance, bone development, and vasculogenesis, among many other processes (Arthur & Gronthos, 2021; Cramer & Miko, 2016; Kania & Klein, 2016; Klein, 2012). Eph-ephrin signaling has also been implicated in numerous cancers (Astin et al, 2010; Merlos-Suárez & Batlle, 2008).…”

Section: Resultsmentioning

confidence: 99%

Combinatorial expression motifs in signaling pathways

Granados

Kanrar

Elowitz

2022

Preprint

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Cell-cell signaling pathways comprise sets of variant receptors that are expressed in different combinations in different cell types. This architecture allows one pathway to be used in a variety of configurations, which could provide distinct functional capabilities, such as responding to different ligand variants. While individual pathways have been well-studied, we have lacked a comprehensive understanding of what receptor combinations are expressed and how they are distributed across cell types. Here, combining data from multiple single-cell gene expression atlases, we analyzed the expression profiles of core signaling pathways, including TGF-β, Notch, Wnt, and Eph-ephrin, as well as non-signaling pathways. In many pathways, a limited set of receptor expression profiles are used recurrently in many distinct cell types. While some recurrent profiles are restricted to groups of closely related cells, others, which we term pathway expression motifs, reappear in distantly related cell types spanning diverse tissues and organs. Motif usage was generally uncorrelated between pathways, remained stable in a given cell type during aging, but could change in sudden punctuated transitions during development. These results suggest a mosaic view of pathway usage, in which the same core pathways can be active in many or most cell types, but operate in one of a handful of distinct modes.

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Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment

Cited by 29 publications

References 187 publications

Single-cell RNA landscape of the osteoimmunology microenvironment in periodontitis

Single-cell RNA landscape of the osteoimmunology microenvironment in periodontitis

Proteomic Comparison of Bone Marrow Derived Osteoblasts and Mesenchymal Stem Cells

Combinatorial expression motifs in signaling pathways

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