Single-Cell Sequencing Unveils the Heterogeneity of Nonimmune Cells in Chronic Apical Periodontitis

Lin, Xinwei; Chi, Danlu; Meng, Qingzhen; Gong, Qimei; Tong, Zhongchun

doi:10.3389/fcell.2021.820274

Cited by 12 publications

(7 citation statements)

References 78 publications

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“…In parallel to composing the healthy tooth atlas, we established a sc transcriptome atlas of diseased human tooth, integrating the at present publicly available datasets from patients with deep caries, enamel caries, chronic apical periodontitis (CAP) and periapical granuloma ( Table 4 ) ( Lin et al, 2022 ; Opasawatchai et al, 2022 ). Following strict quality control, 17,016 cells were retained of which 3,562 and 13,454 cells were derived from dental pulp and periapical diseases (corresponding to the individual datasets), respectively ( Supplementary Figures S3F,G , Table 5 ).…”

Section: Resultsmentioning

confidence: 99%

“…Regarding mouse, single-cell RNA-sequencing (scRNA-seq) datasets were generated from the constantly (re-)growing incisor and the more static, human-resembling molar at different timepoints, either of whole tooth or specific tissue components ( Sharir et al, 2019 ; Takahashi et al, 2019 ; Chen et al, 2020 ; Chiba et al, 2020 , 2021 ; Krivanek et al, 2020 ; Wen et al, 2020 ; Nagata et al, 2021 ; Zhao et al, 2021 ). Human sc transcriptomic data were predominantly generated from dental pulp and periodontal tissues of molars in both healthy and diseased states ( Krivanek et al, 2020 ; Pagella et al, 2021b ; Shi et al, 2021 ; Yin et al, 2021 ; Hemeryck et al, 2022 ; Lin et al, 2022 ; Opasawatchai et al, 2022 ). All these sc analyses generated deeper insight into the tooth molecular and cellular landscape, furthering the understanding of dental cell type heterogeneity and tooth biology.…”

Section: Introductionmentioning

confidence: 99%

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Establishment of inclusive single-cell transcriptome atlases from mouse and human tooth as powerful resource for dental research

Hermans

Bueds

Hemeryck

et al. 2022

Front. Cell Dev. Biol.

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Single-cell (sc) omics has become a powerful tool to unravel a tissue’s cell landscape across health and disease. In recent years, sc transcriptomic interrogation has been applied to a variety of tooth tissues of both human and mouse, which has considerably advanced our fundamental understanding of tooth biology. Now, an overarching and integrated bird’s-view of the human and mouse tooth sc transcriptomic landscape would be a powerful multi-faceted tool for dental research, enabling further decipherment of tooth biology and development through constantly progressing state-of-the-art bioinformatic methods as well as the exploration of novel hypothesis-driven research. To this aim, we re-assessed and integrated recently published scRNA-sequencing datasets of different dental tissue types (healthy and diseased) from human and mouse to establish inclusive tooth sc atlases, and applied the consolidated data map to explore its power. For mouse tooth, we identified novel candidate transcriptional regulators of the ameloblast lineage. Regarding human tooth, we provide support for a developmental connection, not advanced before, between specific epithelial compartments. Taken together, we established inclusive mouse and human tooth sc atlases as powerful tools to potentiate innovative research into tooth biology, development and disease. The maps are provided online in an accessible format for interactive exploration.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Establishment of inclusive single-cell transcriptome atlases from mouse and human tooth as powerful resource for dental research

Hermans

Bueds

Hemeryck

et al. 2022

Front. Cell Dev. Biol.

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“…All merged single‐cell data for the samples were projected in two dimensions using Uniform Manifold Approximation and Projection (UMAP). We profiled single‐cell gene expression in 44 746 cells from the periapical lesions and identified eight cell types by referring to the marker genes reported in our previous study (Figure 1a; Figure S2; Lin et al, 2021). The overlap among genes sharing the same enriched ontology term in the identified cell types encouraged us to consider cellular interactions (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

Heterogeneity of T cells in periapical lesions and in vitro validation of the proangiogenic effect of GZMA on HUVECs

Lin

et al. 2023

Int Endodontic J

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AimT cells are key immunomodulatory cells in periapical lesions. This study aimed to explore the roles of T cells in chronic apical periodontitis (CAP) using single‐cell RNA sequencing and to further investigate Granzyme A (GZMA) in angiogenesis regulation.MethodologyA total of five CAP samples were collected for single‐cell RNA sequencing. We performed subcluster and lineage‐tracing analyses for T cells. According to differential gene expression, distinct biological functions enriched in T cells of CAP were presented by gene set enrichment analysis (GSEA) and compared with healthy gingiva (data obtained from the GEO database). CellChat was used to explore potential ligand–receptor interactions between T cells and endothelial cells in CAP. The coculture of primary human umbilical vein endothelial cells (HUVECs) and Jurkat T cells, as well as the addition of GZMA recombinant protein, was used to validate the predicted pair of GZMA and coagulation factor II thrombin receptor (F2R) by RT‐PCR, angiogenesis and migration assays.ResultsA transcriptomic atlas of 44 746 individual cells was constructed from the periapical lesions of five patients with CAP by single‐cell RNA‐seq, and eight cell types were identified. We identified nine subsets of T cells and deciphered the cellular heterogeneity of T cells in CAP at the functional level by subclustering and GSEA. Lineage tracing revealed a distinct lineage of T cells in CAP and predicted the transition of the T cellular state upon CAP. GSEA revealed multiple biological processes and relevant angiogenesis genes upregulated in CAP T cells. GZMA‐F2R pairs were predicted by cell–cell interactions in CAP. High expression of GZMA and F2R was observed in the coculture of HUVECs and Jurkat T cells, and the proangiogenic capacity of the GZMA recombinant protein was emphasized by in vitro experiments.ConclusionsOur study provides novel insights into the heterogeneity of T cells in periapical lesions and reveals the potential role of GZMA in T cells in regulating angiogenesis in HUVECs.

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“…Notch signaling has been identified as a trigger for keratinocyte differentiation and a key component in the interaction between melanocytes and surrounding keratinocytes [34][35][36] . Although initially found in skin's nonimmune cells, MIF (macrophage migration inhibitory factor), GRN (granulin precursor), and COPA (COPI coat complex subunit alpha) were associated with tumorigenesis and inflammatory diseases [37][38][39] . Additionally, the interaction between CD44 and members of the EGFR and FGFR family of receptor tyrosine kinases (RTKs) on melanocytes to LAMB3+ keratinocytes was upregulated.…”

Section: Discussionmentioning

confidence: 99%

Single-cell sequencing reveals increased LAMB3-positive basal keratinocytes and ZNF90-positive fibroblasts in autologous cultured epithelium

Lian,

Zeng,

et al. 2024

Commun Biol

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Autologous cultured epithelium grafting (ACEG) presents a promising treatment for refractory vitiligo, yet concerns regarding infections and immunological reactions hinder its surgical use due to serum and feeder dependencies. Addressing this, we culture autologous epithelium under serum- and feeder-free (SFF) conditions, comparing its safety and efficacy with serum- and feeder-dependent (SFD) conditions in stable vitiligo patients, and we discover no significant differences in repigmentation between the SFF and SFD grafts. Single-cell RNA transcriptomics on SFF- and SFD-cultured epithelium alongside healthy skin reveal increased populations of LAMB3+ basal keratinocytes and ZNF90+ fibroblasts in the SFF sheets. Functional analyses showcase active cellular metabolism in LAMB3+ basal keratinocytes, vital in extracellular matrix homeostasis, while ZNF90+ fibroblasts demonstrate increased differentiation, essential in collagen formation for cell adhesion. Importantly, these cell populations in SFF sheets exhibit enhanced interactions with melanocytes compared to SFD sheets. Further, knockdown experiments of LAMB3 in keratinocytes and ZNF90 in fibroblasts lead to a downregulation in melanocyte ligand-receptor-related genes. Overall, SFF sheets demonstrate comparable efficacy to SFD sheets, offering superior safety. LAMB3+ basal keratinocytes and ZNF90+ fibroblasts act as potential drivers behind repigmentation in ACEG under SFF conditions. This study provides translational insights into ACEG repigmentation and potential therapeutic targets for vitiligo.

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Single-Cell Sequencing Unveils the Heterogeneity of Nonimmune Cells in Chronic Apical Periodontitis

Cited by 12 publications

References 78 publications

Establishment of inclusive single-cell transcriptome atlases from mouse and human tooth as powerful resource for dental research

Establishment of inclusive single-cell transcriptome atlases from mouse and human tooth as powerful resource for dental research

Heterogeneity of T cells in periapical lesions and in vitro validation of the proangiogenic effect of GZMA on HUVECs

Single-cell sequencing reveals increased LAMB3-positive basal keratinocytes and ZNF90-positive fibroblasts in autologous cultured epithelium

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