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Article Open Access

Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging

  • Authors:
    • Yanfang Du
    • Congyu Zhou
    • Yanpeng Tian
    • Zhongkang Li
    • Xianghua Huang

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    Affiliations: Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
    Copyright: © Du et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 245
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    Published online on: July 3, 2026
       https://doi.org/10.3892/ijmm.2026.5916
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Abstract

Ovarian aging is a key cause of reproductive decline in women. Chronic inflammation and granulosa cell (GC) senescence are implicated in this process; however, the underlying cell‑type‑specific changes and regulatory mechanisms remain incompletely understood. The present study thus aimed to provide insight into these mechanisms. For this purpose, publicly available single‑cell transcriptomic data from human ovarian tissues in the Gene Expression Omnibus database (GSE202601) were analyzed, including four young donors (23‑29 years of age) and four aged donors (49‑54 years of age). Following quality control and integration, clustering, CellChat, pseudotime and SCENIC analyses were performed to define age‑related changes in cellular composition, intercellular communication and transcriptional regulation. Key findings were further supported by complementary in vivo and in vitro experiments in the ovaries of young and aged mice and primary GCs. Integrated analysis revealed marked age‑related shifts in ovarian cellular composition, including the enrichment of a pro‑inflammatory NLRP3+ macrophage subpopulation and a senescence‑associated GC subtype in aged ovaries. Cell‑cell communication analysis suggested enhanced immune‑endocrine crosstalk in aged ovaries, with increased IL‑1β‑IL‑1R1 signaling between macrophages and GCs. Pseudotime and transcriptional regulatory network analyses identified Wilms' tumor 1 (WT1) as a candidate transcription factor upregulated in aged GCs and positively associated with p21 expression, suggesting a potential role in senescence‑associated cell cycle arrest. Experimental validation further supported increased inflammatory signaling, oxidative stress and the activation of the WT1/p21 axis in aged ovaries. On the whole, these findings provide a high‑resolution single‑cell framework for understanding human ovarian aging and suggest that inflammatory signaling and WT1‑associated transcriptional reprogramming may contribute to GC senescence and ovarian functional decline.
View Figures

Figure 1

Construction of a single-cell atlas of human ovarian aging. (A) UMAP plot of 42,261 single-nucleus transcriptomes from young and aged human ovarian tissues, revealing 20 transcriptionally distinct clusters. (B) Dot plot illustrating the expression of canonical marker genes across eight annotated ovarian cell types, including GCs, theca cells, macrophages, epithelial cells, fibroblasts, smooth muscle cells, stromal cells and T-cells. Dot size indicates the proportion of expressing cells, and color intensity indicates average expression. (C) UMAP plot colored by annotated cell type identity. (D) UMAP projections of young and aged ovarian samples shown separately, highlighting age-associated shifts in cellular composition, including reduced GC abundance in aged ovaries. GCs, granulosa cells; TC, theca cells; M, macrophages; EpiC, epithelial cells; F, fibroblasts; SMC, smooth muscle cells; SC, stromal cells.

Figure 2

Marker-based annotation and cell-type composition of human ovarian aging. (A) Feature plots demonstrating representative marker gene expression used to define major ovarian cell types. (B) Violin plots displaying expression levels of selected marker genes across cell types. (C) Heatmap of differentially expressed genes across cell types, validating transcriptional identities. (D) Bar plot illustrating the relative proportions of each cell type in young vs. aged ovaries. GC, granulosa cell; TC, theca cell; M, macrophage; EpiC, epithelial cell; F, fibroblast; SMC, smooth muscle cell; SC, stromal cell; EC, endothelial cell.

Figure 3

Enhanced macrophage-granulosa cell communications and increased IL-1β signaling in aged ovaries. (A) Bar plots illustrating the number and total strength of intercellular interactions in young and aged ovaries. (B) Heatmaps displaying differential interaction number (left panel) and interaction strength (right panel) between cell types. (C) Chord diagrams illustrating the number of interactions among major cell types in young (left panel) and aged (right panel) ovaries. (D) Bar plots illustrating age-dependent changes in pathway-level signaling, including relative and absolute information flow. (E) Heatmaps of IL-1β signaling interactions across cell types in young (left panel) and aged (right panel) ovaries. (F) Dot plot illustrating increased IL-1β-IL-1R1 ligand-receptor signaling between macrophages and granulosa cells in aged ovaries. Circle size and color intensity reflect communication probability.

Figure 4

Identification and characterization of a pro-inflammatory NLRP3+ macrophage subpopulation in aged ovaries. (A) t-SNE plot demonstrating three transcriptionally distinct macrophage subclusters, with cluster 0 predominantly enriched in aged ovaries. (B) t-SNE and heatmap analyses illustrating an elevated expression of NLRP3 in cluster 0. (C) Scatter plot showing the distribution of NLRP3 expression across macrophage subclusters, with higher NLRP3 expression observed in cluster 0. (D) Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of cluster 0-specific genes, highlighting pathways related to interleukin signaling and monocyte differentiation. (E) Pseudotime trajectory illustrating the developmental progression of macrophages, with aged macrophages occupying a terminal state. (F) Pseudotime expression dynamics illustrating the progressive upregulation of NLRP3, together with a violin plot demonstrating the increased expression of NLRP3 in aged samples. (G) Western blot analysis of NLRP3, pro-IL-1β and ASC in young and aged mouse ovarian tissues. (H) Reverse transcription-quantitative PCR analysis demonstrating increased mRNA levels of NLRP3, ASC and IL-1β in aged samples. Data are presented as the mean ± SEM. ***P<0.001. Western blot images shown are representative of three independent biological replicates per group. NLRP3, nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain containing 3; ASC, apoptosis-associated speck-like protein containing a CARD (ASC; formerly known as PYCARD.

Figure 5

Identification and functional characterization of a senescent GC subpopulation in aged ovaries. (A) t-SNE plots demonstrating granulosa cell clustering into eight transcriptionally distinct subclusters, with cluster 4 enriched in aged ovaries. (B) t-SNE plots highlighting the distribution of granulosa cells from young and aged ovaries. (C) Expression profiles of functional genes (NR5A2, LINGO2, and RIMS2) and senescence-associated genes (LAMA2 and ADAMTS9-AS2) in GC_Young and GC_Aged subtypes. (D) Bar plot demonstrating subtype composition in young and aged ovaries, indicating predominance of GC_Aged in aged samples. (E) UMAP plots illustrating increased LAMA2 expression and reduced NR5A2 expression in aged granulosa cells. (F) Immunofluorescence staining for FSHR confirming granulosa cell identity in primary cultures; nuclei were counterstained with DAPI. Scale bar, 100 µm. (G) Senescence-associated β-galactosidase staining demonstrating increased cellular senescence in granulosa cells isolated from aged ovaries. GC, granulosa cell; FSHR, follicle-stimulating hormone receptor.

Figure 6

Pseudotime and SCENIC analyses identify WT1 as a candidate regulator of granulosa cell senescence. (A) Pseudotime trajectory analysis of granulosa cells showing aged cells concentrated at terminal differentiation states. (B) Density distribution of young and aged granulosa cells along pseudotime. (C) SCENIC analysis identifying transcription factors with increased activity in aged granulosa cells, with WT1 among the top age-associated regulators. (D) t-SNE plots illustrating the increased expression of WT1 in aged granulosa cells. (E) Violin plots illustrating elevated WT1 expression in granulosa and fibroblast populations of aged ovaries. (F) Co-expression analysis illustrating a positive association between WT1 and p21 in aged granulosa cells.

Figure 7

Experimental validation of aging-associated ovarian changes in mice. (A) EdU immunofluorescence staining (Azide 555, red) and Hoechst nuclear staining (blue) showing reduced granulosa cell proliferation in aged ovaries. Scale bar, 50 µm. (B) TUNEL staining showing increased apoptotic cell death in aged ovarian tissues; nuclei were counterstained with DAPI (blue). Scale bar, 50 µm. (C) Representative hematoxylin and eosin-stained ovarian sections and quantitative analysis of follicle counts at different developmental stages (primordial to atretic). Scale bar, 200 µm. (D) Serum AMH, FSH and E2 levels measured using ELISA in young and aged mice. (E) Masson's trichrome staining showing enhanced fibrosis in aged ovaries. Scale bar, 200 µm. (F) Immunohistochemical staining showing increased NLRP3 expression in follicles of aged ovaries. Scale bar, 50 µm. (G) Western blot analysis demonstrating the decreased expression of antioxidant enzymes SOD1, IDH1 and GSTP1 in aged ovaries. (H) Western blot analysis demonstrating the increased expression of NLRP3 and IL-1β in aged ovaries, with densitometric quantification normalized to GAPDH. (I) Reverse transcription-quantitative PCR analysis demonstrating the decreased mRNA expression of SOD1 and GSTP1, and the increased expression of NLRP3 and IL-1β in aged ovarian tissues. Data are presented as the mean ± SEM. *P<0.05, **P<0.01 and ***P<0.001. Experiments shown in were independently repeated at least three times. Western blot analyses (G and H) were performed using at least three independent biological replicates per group. Western blot images shown are representative of three independent biological replicates per group. NLRP3, nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain containing 3; IDH1, isocitrate dehydrogenase 1; GSTP1, glutathione S-transferase P 1.

Figure 8

In vivo validation of WT1/p21 activation in aged ovarian granulosa cells. (A) Western blot analysis showing increased WT1 and p21 protein levels in aged granulosa cells. (B) Immunohistochemistry illustrating the elevated expression of p21 in the granulosa cell layer of aged ovarian follicles. Scale bar, 50 µm. (C) Immunofluorescence staining illustrating increased WT1 expression in aged ovarian tissues; nuclei were counterstained with Hoechst. Scale bar, 100 µm. (D) Reverse transcription-quantitative PCR analysis demonstrating the increased mRNA levels of WT1 and CDKN1A (p21) in aged ovaries. Data are presented as mean ± SEM. ***P<0.001. Experiments shown were independently repeated at least three times. Western blot analysis (A) was performed using three independent biological replicates per group. Western blot images shown are representative of three independent biological replicates per group.
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Copy and paste a formatted citation
Spandidos Publications style
Du Y, Zhou C, Tian Y, Li Z and Huang X: Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging. Int J Mol Med 58: 245, 2026.
APA
Du, Y., Zhou, C., Tian, Y., Li, Z., & Huang, X. (2026). Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging. International Journal of Molecular Medicine, 58, 245. https://doi.org/10.3892/ijmm.2026.5916
MLA
Du, Y., Zhou, C., Tian, Y., Li, Z., Huang, X."Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging". International Journal of Molecular Medicine 58.3 (2026): 245.
Chicago
Du, Y., Zhou, C., Tian, Y., Li, Z., Huang, X."Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging". International Journal of Molecular Medicine 58, no. 3 (2026): 245. https://doi.org/10.3892/ijmm.2026.5916
Copy and paste a formatted citation
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Spandidos Publications style
Du Y, Zhou C, Tian Y, Li Z and Huang X: Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging. Int J Mol Med 58: 245, 2026.
APA
Du, Y., Zhou, C., Tian, Y., Li, Z., & Huang, X. (2026). Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging. International Journal of Molecular Medicine, 58, 245. https://doi.org/10.3892/ijmm.2026.5916
MLA
Du, Y., Zhou, C., Tian, Y., Li, Z., Huang, X."Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging". International Journal of Molecular Medicine 58.3 (2026): 245.
Chicago
Du, Y., Zhou, C., Tian, Y., Li, Z., Huang, X."Single‑cell atlas reveals a Wilms' tumor 1‑mediated axis driving granulosa cell senescence in human ovarian aging". International Journal of Molecular Medicine 58, no. 3 (2026): 245. https://doi.org/10.3892/ijmm.2026.5916
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