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Background <p>Endometriosis encompasses heterogeneous lesions, primarily peritoneal and ovarian subtypes, with distinct immunological and fibrotic features. The subtype-specific roles of the immune microenvironment in pathogenesis remain unclear. Integrated analysis combining high-resolution cellular atlases with spatial context is needed to decipher these mechanisms.</p> Methods <p>We performed an integrative analysis of published single-cell RNA sequencing (<i>n</i> = 81,676 cells) from control endometrium (Ctrl), eutopic endometrium (EuE), peritoneal endometriosis (EcP), and ovarian endometriosis (EcO), and spatial transcriptomic (<i>n</i> = 60 segments) data from Ecp and match EuE. Analytical pipelines include cellular atlas construction, differential expression, spatial co-expression, and cell-cell communication inference.</p> Results <p>Our single-cell atlas revealed fundamentally distinct cellular ecosystems. EcP was enriched for <i>CCL19</i> + perivascular cells (6.4-fold vs. control) and immune-active niches, whereas EcO exhibited pronounced smooth muscle differentiation and NNMT upregulation. Spatial analysis compartmentalized these programs, with the <i>CCL19</i>-<i>CCR7</i> chemokine axis localized to stromal niches in EcP strongly correlated (ρ = 0.872). In contrast, EcO showed enhanced smooth muscle gene expression (<i>MYH11</i>, log₂FC = 3.87). Cell-cell communication networks diverged, with EcP dominated by chemokine and TGF-β signaling, and EcO dominated by smooth muscle and PDGF pathways. Therapeutic target analysis revealed subtype-specific patterns: immune checkpoints (<i>CTLA4</i> and <i>PDCD1</i>) were upregulated in EcP, whereas <i>MMP9</i> was dramatically downregulated in EcO.</p> Conclusion <p>EcP and EcO exhibit fundamentally divergent programs. We propose to conceptualize these as an ‘immune-hot’, chemokine-driven inflammatory niche (EcP) versus an ‘immune-cold’, fibromuscular survival niche (EcO). These findings underscore that lesion-specific immune-stromal crosstalk may dictates pathogenesis and suggest a potential paradigm shift toward immunologically-informed, subtype-specific precision therapeutics, which warrant further experimental validation.</p>

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Integrated single-cell and spatial transcriptomics reveal divergent immunological and stromal programs in peritoneal versus ovarian endometriosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Fangjie He,
  • Shuiling Zu,
  • Yan Lin,
  • Jun Shi,
  • Shunhe Lin

摘要

Background

Endometriosis encompasses heterogeneous lesions, primarily peritoneal and ovarian subtypes, with distinct immunological and fibrotic features. The subtype-specific roles of the immune microenvironment in pathogenesis remain unclear. Integrated analysis combining high-resolution cellular atlases with spatial context is needed to decipher these mechanisms.

Methods

We performed an integrative analysis of published single-cell RNA sequencing (n = 81,676 cells) from control endometrium (Ctrl), eutopic endometrium (EuE), peritoneal endometriosis (EcP), and ovarian endometriosis (EcO), and spatial transcriptomic (n = 60 segments) data from Ecp and match EuE. Analytical pipelines include cellular atlas construction, differential expression, spatial co-expression, and cell-cell communication inference.

Results

Our single-cell atlas revealed fundamentally distinct cellular ecosystems. EcP was enriched for CCL19 + perivascular cells (6.4-fold vs. control) and immune-active niches, whereas EcO exhibited pronounced smooth muscle differentiation and NNMT upregulation. Spatial analysis compartmentalized these programs, with the CCL19-CCR7 chemokine axis localized to stromal niches in EcP strongly correlated (ρ = 0.872). In contrast, EcO showed enhanced smooth muscle gene expression (MYH11, log₂FC = 3.87). Cell-cell communication networks diverged, with EcP dominated by chemokine and TGF-β signaling, and EcO dominated by smooth muscle and PDGF pathways. Therapeutic target analysis revealed subtype-specific patterns: immune checkpoints (CTLA4 and PDCD1) were upregulated in EcP, whereas MMP9 was dramatically downregulated in EcO.

Conclusion

EcP and EcO exhibit fundamentally divergent programs. We propose to conceptualize these as an ‘immune-hot’, chemokine-driven inflammatory niche (EcP) versus an ‘immune-cold’, fibromuscular survival niche (EcO). These findings underscore that lesion-specific immune-stromal crosstalk may dictates pathogenesis and suggest a potential paradigm shift toward immunologically-informed, subtype-specific precision therapeutics, which warrant further experimental validation.