Clinical and single-cell integration identifies a TCF21-associated stromal death–inflammation signature in endometriosis

Wangshu Li, Xiuying Wang, Aziz ur Rehman Aziz, Jiuxiang Feng, Chunfang Ha
In: Frontiers in Cell and Developmental Biology · 2026 · vol. 14 · doi:10.3389/fcell.2026.1979976 · W7225311905
OA: gold CC0
🔓 Open OA copy View on OpenAlex View at publisher

Abstract

Background Stromal heterogeneity, regulated-cell-death-associated stress, and chronic inflammation contribute to endometriosis, but their relationships within specific stromal populations remain incompletely understood. This study integrated clinical characterization with single-cell and spatial transcriptomics to investigate a TCF21-associated stromal death–inflammation signature. Methods A retrospective cohort of 150 patients with histopathologically confirmed endometriosis was characterized clinically. Public single-cell datasets (GSE179640 and GSE213216) were analyzed to identify stromal populations, reconstruct transcriptional trajectories, evaluate death-associated and inflammatory programs, and infer intercellular communication. Spatial transcriptomic analysis assessed TCF21-associated expression patterns in endometriotic lesions. Multiplex immunofluorescence, RT-qPCR, TCF21 silencing, EdU incorporation, Transwell assays, and three-dimensional spheroid culture were used for experimental evaluation. Results Single-cell analysis identified 13 major cell classes and a fib-TCF21-associated stromal state characterized by TCF21, NEXN, IFI44L, WNT2B, and SPRR2F. Cell-death-associated and inflammatory transcriptional programs varied across stromal states, with fib-TCF21 exhibiting selective rather than uniformly elevated program activity. Independent single-cell analysis identified a related but anatomically heterogeneous stromal expression pattern. Spatial transcriptomics demonstrated localized TCF21 expression and heterogeneous distributions of stromal, stress-associated, and inflammatory programs. Tissue immunofluorescence supported stromal-associated TCF21 expression, while lesion-derived ihESCs exhibited higher basal TCF21 expression than the eutopic stromal-cell model. TCF21 silencing was associated with reduced EdU incorporation, Transwell membrane traversal, and three-dimensional spheroid growth. Conclusion Integration of clinical, single-cell, spatial, and experimental findings identifies a TCF21-associated stromal transcriptional signature linked to heterogeneous death-related stress and inflammatory programs in endometriosis. These findings support further investigation of TCF21-associated stromal biology and its potential relevance to molecularly targeted interventions.

My notes (saved in your browser only)

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (37)

Source provenance

openalex
last seen: 2026-11-07T06:05:52.158007+00:00
License: CC0 · commercial use OK