Frontiers in immunology · 2026
Single-cell landscape of lymphoid and myeloid heterogeneity across type-stratified craniofacial lesions in polyostotic fibrous dysplasia.
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Duan Hui-Chuan, Liang Xia, Wang De-Cheng, Yuan Jie, Yang Fan
Аннотация
BACKGROUND: Polyostotic fibrous dysplasia (POFD) is a mosaic skeletal disorder driven by somatic GNAS mutations that constitutively activate Gsα-cAMP signaling, producing fibro-osseous craniofacial deformities. POFD lesions are histologically classified into three subtypes-Type I (connective-tissue predominant), Type II (cancellous-bone predominant), and Type III (sclerotic-bone predominant)-yet the immune microenvironment across these categories remains undefined. This study aims to dissect lymphoid and myeloid heterogeneity and inter-cellular communication networks among distinct POFD histological categories.
METHODS: We performed single-cell RNA sequencing on maxillary lesion tissues from three age- and sex-matched POFD patients classified as Type I (n=1), Type II (n=1), and Type III (n=1). After stringent quality control, 24,567 cells (median 1,762 genes/cell) were integrated and clustered. Ligand-receptor interactions were inferred using CellChat.
RESULTS: Four major lineages were resolved: mesenchyme, lymphoid, myeloid, endovascular. Lymphoid representation differed across subtypes (Type I 1.00%, Type II 5.10%, Type III 10.90%), whereas endovascular fractions showed an inverse pattern (Type I 25.10%, Type II 9.90%, Type III 4.50%). Sub-clustering identified five lymphoid and six myeloid subsets. CD4+ T cells were most abundant in Type I (51.10%) but less represented in Type II (36.50%) and Type III (29.30%). CD8+ T cells constituted 2.10%, 11.90%, and 11.20% across Types I-III, respectively; germinal-center (GC) B cells were undetectable in Type I, minor in Type II (~1.60%), and prominent in Type III (~29.20%). Among myeloid cells, M1 macrophages comprised 9.90% in Type I, 25.70% in Type II, and 15.30% in Type III; osteoclasts were abundant in Type I (35.40%) but scarce in Types II and III (<5%). Dendritic cells (DCs) were absent in Type I yet detectable in Type II (1.90%) and Type III (2.60%). Network-central genes included LTB, TXNIP, FTH1, and PABPC1 for CD4+ and GC B cells, and S100A8/9, CXCL8, CCL2/3/4, and IL1B for M1 macrophages and monocytes. Inter-cellular communication networks differed markedly by subtype: Type I and II displayed relatively simple interactomes, whereas Type III exhibited densely interconnected signaling with strengthened M2 macrophage-monocyte, M2 macrophage-GC B cell (CXCL12-CXCR4, APP-CD74), and GC B cell-monocyte axes, alongside attenuated CD4+ T cell-GC B cell (CLEC2D-KLRB1, ADGRE5-CD55) and M1 macrophage-CD4+ T cell crosstalk. Pathway enrichment revealed subtype-specific activation of oxidative phosphorylation, NF-κB, and antigen-presentation cascades across lymphoid and myeloid compartments.
CONCLUSIONS: This study provides the first single-cell immune atlas of POFD, delineating lymphoid and myeloid heterogeneity across three histological subtypes. The identified subtype-specific markers and inter-cellular communication architectures offer candidate biomarkers for diagnostic stratification and reveal potential immunomodulatory targets for this disfiguring bone disorder.
METHODS: We performed single-cell RNA sequencing on maxillary lesion tissues from three age- and sex-matched POFD patients classified as Type I (n=1), Type II (n=1), and Type III (n=1). After stringent quality control, 24,567 cells (median 1,762 genes/cell) were integrated and clustered. Ligand-receptor interactions were inferred using CellChat.
RESULTS: Four major lineages were resolved: mesenchyme, lymphoid, myeloid, endovascular. Lymphoid representation differed across subtypes (Type I 1.00%, Type II 5.10%, Type III 10.90%), whereas endovascular fractions showed an inverse pattern (Type I 25.10%, Type II 9.90%, Type III 4.50%). Sub-clustering identified five lymphoid and six myeloid subsets. CD4+ T cells were most abundant in Type I (51.10%) but less represented in Type II (36.50%) and Type III (29.30%). CD8+ T cells constituted 2.10%, 11.90%, and 11.20% across Types I-III, respectively; germinal-center (GC) B cells were undetectable in Type I, minor in Type II (~1.60%), and prominent in Type III (~29.20%). Among myeloid cells, M1 macrophages comprised 9.90% in Type I, 25.70% in Type II, and 15.30% in Type III; osteoclasts were abundant in Type I (35.40%) but scarce in Types II and III (<5%). Dendritic cells (DCs) were absent in Type I yet detectable in Type II (1.90%) and Type III (2.60%). Network-central genes included LTB, TXNIP, FTH1, and PABPC1 for CD4+ and GC B cells, and S100A8/9, CXCL8, CCL2/3/4, and IL1B for M1 macrophages and monocytes. Inter-cellular communication networks differed markedly by subtype: Type I and II displayed relatively simple interactomes, whereas Type III exhibited densely interconnected signaling with strengthened M2 macrophage-monocyte, M2 macrophage-GC B cell (CXCL12-CXCR4, APP-CD74), and GC B cell-monocyte axes, alongside attenuated CD4+ T cell-GC B cell (CLEC2D-KLRB1, ADGRE5-CD55) and M1 macrophage-CD4+ T cell crosstalk. Pathway enrichment revealed subtype-specific activation of oxidative phosphorylation, NF-κB, and antigen-presentation cascades across lymphoid and myeloid compartments.
CONCLUSIONS: This study provides the first single-cell immune atlas of POFD, delineating lymphoid and myeloid heterogeneity across three histological subtypes. The identified subtype-specific markers and inter-cellular communication architectures offer candidate biomarkers for diagnostic stratification and reveal potential immunomodulatory targets for this disfiguring bone disorder.