Comparative analysis reveals distinct molecular heterogeneity in vaginal cells between recurrent and primary pelvic organ prolapse patients

Abstract

High recurrence rate in pelvic organ prolapse (POP) seriously increases treatment difficulty and elucidating the mechanisms is critical for developing targeted therapies. However, its underlying molecular mechanisms remain unclear. Using a single-cell RNA sequencing dataset, we analyzed vaginal fibroblasts, smooth muscle cells and macrophages in recurrent and primary POP. Comparative analysis of differentially expressed genes (DEGs) showed recurrent and primary POP shared fewer DEGs, while exhibiting more subtype-specific DEGs, confirming substantial molecular heterogeneity. Further analysis revealed that shared fibroblast DEGs in both POP subtypes were primarily enriched in collagen fibril organization, while recurrent POP showed uniquely upregulation of genes related to collagen metabolism and leukocyte migration. NKD2⁺ myofibroblasts were higher in recurrent POP compared to primary POP. In macrophages, shared upregulated DEGs in both groups were enriched in ECM remodeling and TGF-β signaling, highlighting conserved roles of macrophages-fibroblast interaction. Whereas, certain genes, such as fibrotic-related genes, were specifically upregulated in recurrent POP, implicating potential distinct fibrotic mechanisms in recurrence. Furthermore, the proportion of M2-like macrophages in recurrent POP was higher than primary POP. These findings reveal a potential shift toward pro-fibrotic and tissue-remodeling immune microenvironment in recurrent POP, providing novel insights into the cellular and molecular drivers of POP recurrence.

Keywords

POP recurrence / molecular heterogeneity / ECM dysregulation / macrophages

1 Introduction

Pelvic organ prolapse (POP) is one of the most common gynecological benign diseases among middle-aged and elderly women [1,2]. In China, the prevalence rate of POP among women is 9.6%, with its incidence highly correlated with advancing age [3]. The incidence of POP in women aged 50–59 years is 13.4% [4]. The lifetime risk of undergoing POP surgery is 13% [5]. In clinic, the surgery for pelvic floor reconstruction primarily includes autologous tissue transplantation (e.g., uterosacral ligament suspension and sacrospinous ligament suspension) and repair by mesh implantation. Although mesh repair surgeries have a higher anatomical success rate [6], complications are severe such as mesh exposure and pain [7]. Consequently, many countries have banned transvaginal mesh implantation and instead encourage the use of autologous tissue repair. Unfortunately, the recurrence of POP in both mesh repair and autologous tissue repair is relatively high, with approximately 11.5% of women aged 65 years or older requiring reoperation within five years due to POP recurrence [8–11]. Especially, the recurrence rate is even higher in cases of autologous tissue repair [6]. Recurrent prolapse severely aggravates chronic symptoms such as pelvic pain, urinary incontinence, and increases surgical costs and technical challenges due to scar tissue formation. Deciphering the molecular mechanisms is vital for developing targeted interventions to reduce serious complications. However, the etiology and underlying molecular mechanisms in POP recurrence are still unknown.

Currently, most studies on the influencing factors of POP recurrence have primarily focused on clinical indicators [12], such as the severity of prolapse [13], the number of vaginal deliveries, and body mass index [14]. However, these clinical factors alone cannot fully explain the heterogeneity in recurrence rates, prompting investigation into molecular-level contributors. Some studies have identified associated genes such as ADIPOQ and IL6 that may be involved in the mechanism of recurrent prolapse [15]. However, research on the mechanisms underlying POP recurrence remains limited, particularly cell type-specific molecular changes in the vaginal wall tissues. In this study, we utilized an established single-cell RNA sequencing (scRNA-seq) dataset to analyze cell type-specific molecular changes in the anterior vaginal wall tissues of patients with recurrent POP, primary POP, and healthy controls. This work will identify cell type-specific changes in gene expression and signaling pathways that may contribute to POP recurrence. The findings of our study will provide novel insights into the mechanisms of POP recurrence and offer potential therapeutic targets to improve surgical outcomes and reduce recurrence rates.

2 Materials and methods

2.1 Patients and data sources

This study utilized scRNA-seq data from our previously established database, which included vaginal wall tissues from healthy controls and patients with severe POP (GSE151202) [16]. In previous analyses, no distinction was made between primary and recurrent POP cases. For the current study, we selected the following samples for analysis: 5 normal controls (vaginal anterior wall), 5 primary POP patients (vaginal anterior wall from first-time surgery), 3 recurrent POP patients (vaginal anterior wall from reoperation due to recurrent POP). The 5 primary POP patients were selected from an initial pool of 13 primary POP cases in the database. To ensure they could serve as a more robust control group to the recurrent POP group, we conducted follow-up assessments on all 13 primary cases until December 2024. Among them, 3 were lost to follow-up, 5 developed symptomatic recurrence, and the remaining 5 had no symptomatic recurrence during the follow-up period. These 5 non-recurrent patients were thus included in the primary POP group for final analysis. This selection was determined solely by their recurrence status at the end of follow-up, with no predefined matching criteria to the recurrent cases. To ensure data reliability, we first performed quality control and clustering on all patient data in the database following our established pipeline. Subsequently, we re-clustered the selected datasets and extracted fibroblast and macrophage populations for downstream analysis. All patients were postmenopausal, and there were no significantly differences in age or BMI.

2.2 DEGs and enrichment analysis

To find the differentially expressed genes (DEGs), the expression matrix of each cell type generated by scRNA-seq was pseudobulked by the function PseudobulkExpression from Seurat (v5.1.0). Genes with extremely low detection (total UMI counts < 3) were removed followed by standard DESeq2 pipeline (fitType = local, v1.40.2). Genes with |log₂FC| > 1 and P-value < 0.05 were identified as DEGs. All the identified DEGs were significantly changed according to FindMarkers function from Seurat (adjusted P-value < 0.05, Wilcox test followed by BH adjustment). To perform the Gene Ontology (GO) and KEGG pathway enrichment analysis of DEGs, clusterProfiler (v4.7.1.003) and database org.Hs.eg.db (v3.17.0) were used with the default parameters. To perform the Gene Set Enrichment Analysis (GSEA), shrinkage of pseudobulked data was first performed by lfcShrink function from DESeq2 (type = normal) to minimize the disturbance of low-expressed genes. Then the enrichments were performed with clusterProfiler. GO terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with adjusted P-value < 0.05 were identified as significantly enriched terms.

2.3 Cell subtype analysis

For a given cell type, the expression matrix of each sample was first normalized and scaled, followed by identification of 2000 variable features and PCA with Seurat (v5.1.0). Then the datasets were integrated using the function IntegrateLayers (method = CCAIntegration) following a standard Seurat pipeline. Samples with less than 100 cells were not included during the integration according to the requirement of the function IntegrateLayers. The integrated data were visualized under UMAP embeddings. Markers of each cell subtype were identified using either the FindMarkers or FindAllMarkers function.

2.4 Statistical analysis

The statistical analysis of clinical characteristics was performed using SPSS, and a P-value < 0.05 was considered statistically significant.

3 Results

3.1 Heterogeneity of DEGs specifically associated with fibroblasts in primary and recurrent POP

Compared with the normal control group, 436 genes were upregulated and 654 genes were downregulated in the recurrent POP group. In the primary POP group, 671 genes were upregulated and 944 genes were downregulated. The number of DEGs in the recurrent group was lower than that in the primary group. Compared with normal controls, genes associated with extracellular matrix (ECM) remodeling and fibrosis, such as COL1A2, COL9A1, FN1, SPARC, BGN, LUM, MMP2, MMP11, MMP14, MMP23B, and LOX, as well as genes related to immunity and chronic inflammation, including IL18, C1QA, were significantly upregulated in the recurrent group. Certain genes, such as KRT1, a gene linked to epithelial-mesenchymal transition (EMT), and LYVE1 related to fibroblast-macrophage interactions, were significantly upregulated in both the recurrent and primary groups (Fig. 1A). Additionally, genes involved in mediating inflammatory responses, such as IL1RL1 and CXCL1, and genes implicated in immune-inflammation regulation and suppression, such as CCL18, were significantly downregulated in the primary group compared with normal controls (Fig. 1B). Gene Ontology (GO) analysis revealed that, compared with the control group, the upregulated genes in the recurrent group were primarily enriched in ECM organization and leukocyte migration, while processes such as ribosome biogenesis were downregulated (Fig. 1C). In the primary group, the upregulated genes were mainly enriched in the regulation of tubular diameter; GO terms such as positive regulation of cell adhesion and embryonic organ development were downregulated (Fig. 1D). Similar GO terms exhibited consistent enrichment trends in GSEA (Fig. S1A). These findings demonstrate divergent molecular pathways between the two prolapse types, despite the conserved roles of chronic inflammation and ECM degradation in POP pathogenesis.

We further performed a comparative analysis of DEGs between the two types of prolapse. Our findings revealed that 169 (18%) genes were upregulated, while 289 (22.1%) genes were downregulated. The number of common DEGs in the two prolapse types was significantly lower than that of unique DEGs, indicating substantial differences in fibroblast type-specific gene expression (Fig. 2A and 2B). The upregulated genes shared by both groups were primarily enriched in collagen fibril organization (Fig. 2C and 2D). In contrast, the specific upregulated genes in the recurrent group were predominantly enriched in ECM organization, collagen metabolic processes (e.g. MMP14, MMP11) and leukocyte migration (e.g. ECM1) (Fig. 2E and 2F). The enriched terms of upregulated genes in the primary group have no significantly difference. These results suggest that while the shared collagen metabolism abnormalities in POP, recurrent POP probably exhibit more severe ECM degradation and inflammatory infiltration, suggesting progressive tissue microenvironment alterations.

3.2 Distribution, similarities and differences of fibroblast subtypes in two different prolapse types

The fibroblasts were further classified into five distinct cell types, namely OGN⁺ Fibroblasts, NKD2⁺ myofibroblasts, acute responded fibroblasts, APOE/GGT5 high fibroblasts, and smooth muscle-like fibroblasts (Fig. 3A and 3B, Table S1). Notably, the proportion of the NKD2⁺ myofibroblast subtype in the recurrent group was higher than that in the primary group, indicating a potential transition from fibroblasts to myofibroblasts during prolapse recurrence (Fig. 3C). Therefore, it is hypothesized that tissue fibrosis may play a more critical role in the pathogenesis of recurrent prolapse than primary prolapse.

3.3 Comparative analysis of macrophage-specific gene expression profiles between primary and recurrent POP

Compared with normal controls, the recurrent group exhibited 421 upregulated genes and 333 downregulated genes in macrophages. In contrast, the primary group demonstrated 374 upregulated genes and 200 downregulated genes. Genes such as LUM, which mediate the interaction between macrophages and fibroblasts, were significantly upregulated in both recurrent prolapse and primary prolapse. Immune- and inflammation-related genes, including CCL8, were also significantly upregulated in both prolapse types (Fig. 4A and 4B). Genes associated with ECM dysregulation were significantly upregulated in both types of prolapse. Consistent with previous observations, these results support the conserved involvement of macrophage-fibroblast interactions in driving ECM pathological remodeling across both prolapse types. GO analysis revealed that genes upregulated in both groups were primarily enriched in the ECM organization pathway (Fig. 4C and 4D). Downregulated genes in the recurrent group were mainly enriched in pathways related to oxidative stress response and wound healing, whereas downregulated genes in the primary group were predominantly enriched in the positive regulation of cytokine production pathway (Fig. 4C and 4D). Similar GO terms exhibited consistent enrichment trends in GSEA (Fig. S1B). These distinct findings suggest that macrophages may participate in recurrent and primary prolapse through divergent molecular pathways, contributing to ECM dysregulation.

3.4 Distinct DEGs and functions between the two different prolapse types

A comparative analysis of the DEGs between the two types of prolapse was further performed. Our results revealed that there were 162 (25.6%) commonly upregulated genes and 97 (22.2%) commonly downregulated genes. The number of common genes was lower than that of unique genes, indicating significant differences in macrophage type-specific DEGs between the two types of prolapse (Fig. 5A and 5B). GO enrichment analysis of the upregulated genes in both types of prolapse demonstrated significant enrichment in pathways such as ECM organization and transforming growth factor-beta receptor signaling (Fig. 5C and 5D). The specific upregulated genes in recurrent POP were mainly enriched in pathways including ECM organization, collagen fibril organization, and connective tissue development (Fig. 5E and 5F). For example, key fibrotic regulators, including LOX (collagen crosslinking), BGN (proteoglycan-mediated scarring), and PDGFRB (fibroblast activation), were significantly upregulated in recurrent POP. The enriched GO terms of upregulated genes in primary POP have no significantly difference. Based on these findings, it can be inferred that macrophages in recurrent POP may promote stronger abnormal collagen metabolism and fibrotic remodeling through distinct molecular pathways than those activated in primary POP.

3.5 Distribution, similarities and differences of macrophage subtypes in two different prolapse types

Macrophage populations were further classified into four distinct cell subsets, including CD1C⁺ dendritic cells, CD163⁺CCR1⁺ (M2-like), CD79B⁺FCGR3A⁺, and CD163⁺CD52⁺ (M1-like) (Fig. 5G and 5H, Table S2). Notably, the proportion of M2-like macrophages subset was elevated in both types of prolapse compared to normal controls, with a significantly higher proportion observed in recurrent prolapse than primary prolapse (Fig. 5I). These findings implicate that M2-like macrophages contribute to immune dysregulation and pathological tissue remodeling in prolapse progression, with particularly prominent involvement in recurrent prolapse.

3.6 Smooth muscle cells transcriptomic features and subtypes in two different prolapse types

Smooth muscle cells in recurrent and primary POP exhibit both shared and distinct transcriptional profiles: compared to controls, both groups showed upregulation of genes associated with collagen fibril organization and ECM organization (e.g., LUM) (Fig. 6A–6F). Similar GO terms exhibited consistent enrichment trends in GSEA (Fig. S1C). Genes enriched in collagen metabolic processes were specifically upregulated in recurrent POP (Fig. 6G and 6H). Subtype analysis identified three smooth muscle cells subsets, including TDO2⁺ smooth muscle cells, whose proportion is higher in recurrent than primary POP (Fig. 6I and 6J, Table S3).

4 Discussion

POP recurrence remains a significant clinical challenge, with high reoperation rates despite advances in surgical techniques [14,17]. However, the underlying molecular mechanisms remain poorly understood. Our study provides the first comprehensive single-cell resolution comparison of vaginal fibroblast and macrophage heterogeneity between recurrent and primary POP, revealing distinct cellular profiles underlying prolapse recurrence. Through comparative transcriptomic analysis, we identified key molecular pathways that differentiate recurrent from primary prolapse. While both POP types exhibit shared fibroblast-mediated mechanisms involving chronic inflammation and ECM organization, recurrent POP demonstrated more severe collagen degradation (e.g., MMP14, MMP11) and inflammatory infiltration (e.g., VEGFB, THBS4). Additionally, macrophages in recurrent POP may promoted stronger abnormal collagen metabolism and fibrotic remodeling through fibrotic-related molecules (LOX, BGN, and PDGFRB) compared to primary POP. These findings correlated with altered macrophage-fibroblast crosstalk, with M2-like macrophages playing a central role in the profibrotic process.

The role of fibroblasts and macrophages in POP progress has been highlighted by their involvement in ECM organization and inflammation regulation in previous studies [16,18–21]. In this study, recurrent prolapse exhibited distinct fibroblast- and macrophage-related gene expression compared with the primary prolapse. Fibroblasts in recurrent POP showed upregulation of genes such as COL1A2, FN1, and MMPs, which are critical for ECM organization and fibrosis, alongside an increased proportion of NKD2⁺ myofibroblasts. Similarly, macrophages in recurrent POP displayed elevated expression of ECM-related genes (e.g., LUM) and a higher proportion of M2-like macrophages, indicating their association with immune regulation and tissue remodeling. These findings further confirmed that chronic inflammation and ECM degradation are critical to POP recurrence, as persistent inflammatory signals may exacerbate fibroblast activation and ECM turnover, ultimately weakening pelvic support structures. The molecular alterations identified in this study may provide significant clinical implications. For instance, the dysregulation of ECM-related genes in fibroblasts suggests that modulating MMP activity or enhancing collagen synthesis while attenuating inflammatory responses could improve tissue repair and reduce recurrence rates. One previous study has reported a multifunctional electrospun patch integrating both anti-inflammatory and pro-collagen synthesis properties, which demonstrated successful tissue regeneration and repair in a POP model [22]. Another study reported that ECM-mimicking hydrogels demonstrated remarkable efficacy in postpartum pelvic floor rehabilitation by orchestrating balanced ECM remodeling and modulating the immune microenvironment, effectively preventing fibrotic complications [23]. These proof-of-concept studies highlight the potential of multi-targeted regenerative strategies for recurrent POP treatment, where coordinated ECM restoration and inflammation control appear crucial for achieving durable therapeutic outcomes.

The distinct transcriptomic profiles of NKD2⁺ myofibroblasts and CD163⁺CCR1⁺ macrophages identified in recurrent POP provide novel insights into the molecular drivers of fibrotic remodeling, with parallels to fibrosis observed in other tissues. NKD2 is a well-characterized inhibitor of Wnt/β-catenin signaling, a pathway critical for regulating cell proliferation, differentiation, and ECM homeostasis across tissues [24]. Our observation of increased NKD2⁺ myofibroblast abundance in recurrent POP aligns with findings by Kuppe et al. [25], who demonstrated that NKD2 is essential for collagen expression in human kidney PDGFRB⁺ cells and acts as a potential therapeutic target in kidney fibrosis. Although our scRNA-seq data did not detect significant changes in the expression of Wnt receptors or ligands between recurrent and primary POP groups, the elevated abundance of NKD2⁺ myofibroblasts themselves suggests a potential disruption of Wnt-mediated ECM, which could promote excessive collagen deposition—a hallmark of fibrosis. Given that Wnt signaling dysfunction is linked to tissue stiffening in liver and lung fibrosis [26,27], our data support a conserved role for NKD2⁺ myofibroblasts in driving fibrotic remodeling in certain POP recurrence cases. CD163⁺CCR1⁺ macrophages similarly contribute to pro-fibrotic microenvironments through immune cell recruitment and paracrine signaling. CCR1, a chemokine receptor, mediates the recruitment of leukocytes, monocytes, and other immune cells to sites of inflammation [28]. In recurrent POP, the enrichment of this subtype may induce inflammatory cell infiltration, accelerate tissue damage, and lead to fibrosis. This aligns with studies in liver fibrosis, where Li et al. [29] demonstrated that CCR1 and its ligand CCL5 (also known as RANTES) form a pro-fibrotic axis, recruiting a variety of inflammatory cells into injured liver. Our findings highlight a pro-fibrotic network in recurrent POP, where increased NKD2⁺ myofibroblasts and CD163⁺CCR1⁺ macrophages synergize to disrupt ECM homeostasis. The enrichment of CCR1⁺ macrophages, in particular, aligns with their established role in promoting fibrosis through enhanced infiltration, offering a potential therapeutic target to mitigate POP recurrence—consistent with emerging strategies targeting CCR1 in liver fibrosis [30,31].

Despite these molecular findings, the study has several limitations. The sample size, particularly for recurrent POP patients, was relatively small, which may limit the generalizability of the findings. Future studies with larger cohorts, including diverse patient populations and varied initial surgical procedures, are required to validate these results. Second, our study was observational in nature and unable to establish causality. To confirm the roles of the identified cellular subsets and molecular pathways in recurrent POP, future functional studies, such as in vitro assays and animal model experiments, are warranted.

In summary, this study provides novel mechanistic insights into POP recurrence by systematically characterizing distinct fibroblast, macrophage, and smooth muscle cells molecular signatures that differentiate recurrent from primary POP. Moreover, several dysregulated pathways specifically associated with recurrent prolapse were identified. These findings advance our understanding of POP recurrence pathogenesis and offer potential therapeutic targets for improving surgical outcomes and reducing recurrence rates.

References

[1] Barber MD , Maher C . Epidemiology and outcome assessment of pelvic organ prolapse. Int Urogynecol J 2013; 24(11): 1783–1790

[2] Kinman CL , Lemieux CA , Agrawal A , Gaskins JT , Meriwether KV , Francis SL . The relationship between age and pelvic organ prolapse bother. Int Urogynecol J 2017; 28(5): 751–755

[3] Pang H , Zhang L , Han S , Li Z , Gong J , Liu Q , Liu X , Wang J , Xia Z , Lang J , Xu T , Zhu L . A nationwide population-based survey on the prevalence and risk factors of symptomatic pelvic organ prolapse in adult women in China—a pelvic organ prolapse quantification system-based study. BJOG 2021; 128(8): 1313–1323

[4] Li Z , Xu T , Li Z , Gong J , Liu Q , Zhu L . An epidemiologic study of pelvic organ prolapse in rural Chinese women: a population-based sample in China. Int Urogynecol J 2019; 30(11): 1925–1932

[5] Wu JM , Matthews CA , Conover MM , Pate V , Jonsson Funk M . Lifetime risk of stress urinary incontinence or pelvic organ prolapse surgery. Obstet Gynecol 2014; 123(6): 1201–1206

[6] Menefee SA , Richter HE , Myers D , Moalli P , Weidner AC , Harvie HS , Rahn DD , Meriwether KV , Paraiso MFR , Whitworth R , Mazloomdoost D , Thomas S; NICHD Pelvic Floor Disorders Network . Apical suspension repair for vaginal vault prolapse: a randomized clinical trial. JAMA Surg 2024; 159(8): 845–855

[7] Wihersaari O , Karjalainen P , Tolppanen AM , Mattsson N , Jalkanen J , Nieminen K . Complications of pelvic organ prolapse surgery in the 2015 Finnish Pelvic Organ Prolapse Surgery Survey Study. Obstet Gynecol 2020; 136(6): 1135–1144

[8] Wu JM , Dieter AA , Pate V , Jonsson Funk M . Cumulative incidence of a subsequent surgery after stress urinary incontinence and pelvic organ prolapse procedure. Obstet Gynecol 2017; 129(6): 1124–1130

[9] Maher C , Feiner B , Baessler K , Christmann-Schmid C , Haya N , Brown J . Surgery for women with apical vaginal prolapse. Cochrane Libr 2016; 10(10): CD012376

[10] Kuittinen T , Mentula M , Tulokas S , Brummer T , Jalkanen J , Tomas E , Mäkinen J , Sjöberg J , Härkki P , Rahkola-Soisalo P . Recurrent pelvic organ prolapse after hysterectomy; a 10-year national follow-up study. Arch Gynecol Obstet 2024; 310(5): 2705–2715

[11] Brunes M , Johannesson U , Drca A , Bergman I , Söderberg M , Warnqvist A , Ek M . Recurrent surgery in uterine prolapse: a nationwide register study. Acta Obstet Gynecol Scand 2022; 101(5): 532–541

[12] Vergeldt TF , Weemhoff M , IntHout J , Kluivers KB . IntHout J, Kluivers KB. Risk factors for pelvic organ prolapse and its recurrence: a systematic review. Int Urogynecol J 2015; 26(11): 1559–1573

[13] Bodner-Adler B , Bodner K , Carlin G , Kimberger O , Marschalek J , Koelbl H , Umek W . Clinical risk factors for recurrence of pelvic organ prolapse after primary native tissue prolapse repair. Wien Klin Wochenschr 2022; 134(1–2): 73–75

[14] Schulten SFM , Claas-Quax MJ , Weemhoff M , van Eijndhoven HW , van Leijsen SA , Vergeldt TF , IntHout J , Kluivers KB . Risk factors for primary pelvic organ prolapse and prolapse recurrence: an updated systematic review and meta-analysis. Am J Obstet Gynecol 2022; 227(2): 192–208

[15] Zhou Q , Lu M , Li GS , Peng GL , Song YF . Identification of potential molecular mechanisms and therapeutic targets for recurrent pelvic organ prolapse. Heliyon 2023; 9(9): e19440

[16] Li Y , Zhang QY , Sun BF , Ma Y , Zhang Y , Wang M , Ma C , Shi H , Sun Z , Chen J , Yang YG , Zhu L . Single-cell transcriptome profiling of the vaginal wall in women with severe anterior vaginal prolapse. Nat Commun 2021; 12(1): 87

[17] Campagna G , Vacca L , Lombisani A , Panico G , Caramazza D , Mastrovito S , Ercoli A , Scambia G . Recurrent pelvic prolapse after pelvic organ prolapse suspension (POPS): Analysis and treatment of an emerging clinical issue. Eur J Obstet Gynecol Reprod Biol 2024; 302: 1–6

[18] Tian Z , Li Q , Wang X , Sun Z . The difference in extracellular matrix metabolism in women with and without pelvic organ prolapse: A systematic review and meta-analysis. BJOG 2024; 131(8): 1029–1041

[19] Wu C , Zhou Z , Yang Y , Li H , Guo Y , Tong X . Bioinformatically deciphering immune cell infiltration and signature genes in pelvic organ prolapse. Int Urogynecol J 2023; 34(5): 1091–1101

[20] Orlicky DJ , Guess MK , Bales ES , Rascoff LG , Arruda JS , Hutchinson-Colas JA , Johnson J , Connell KA . Using the novel pelvic organ prolapse histologic quantification system to identify phenotypes in uterosacral ligaments in women with pelvic organ prolapse. Am J Obstet Gynecol 2021; 224(1): 67.e1–67.e18

[21] Chen Y , Ullah A , Chen W , Xuan J , Huang X , Liang S , Shen B , Wu T . Cytokine modulation in pelvic organ prolapse and urinary incontinence: from molecular insights to therapeutic targets. Mol Med 2024; 30(1): 214

[22] Zhang D , Xu D , Huang X , Wei Y , Tang F , Qin X , Liang W , Liang Z , Jin L , Wang H , Wang H . Puerarin-loaded electrospun patches with anti-inflammatory and pro-collagen synthesis properties for pelvic floor reconstruction. Adv Sci (Weinh) 2024; 11(21): 2308590

[23] Duran P , Boscolo Sesillo F , Cook M , Burnett L , Menefee SA , Do E , French S , Zazueta-Damian G , Dzieciatkowska M , Saviola AJ , Shah MM , Sanvictores C , Osborn KG , Hansen KC , Shtrahman M , Christman KL , Alperin M . Proregenerative extracellular matrix hydrogel mitigates pathological alterations of pelvic skeletal muscles after birth injury. Sci Transl Med 2023; 15(707): eabj3138

[24] Hu T , Li C . Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol Cancer 2010; 9(1): 236

[25] Kuppe C , Ibrahim MM , Kranz J , Zhang X , Ziegler S , Perales-Patón J , Jansen J , Reimer KC , Smith JR , Dobie R , Wilson-Kanamori JR , Halder M , Xu Y , Kabgani N , Kaesler N , Klaus M , Gernhold L , Puelles VG , Huber TB , Boor P , Menzel S , Hoogenboezem RM , Bindels EMJ , Steffens J , Floege J , Schneider RK , Saez-Rodriguez J , Henderson NC , Kramann R . Decoding myofibroblast origins in human kidney fibrosis. Nature 2021; 589(7841): 281–286

[26] Patel M , Post Y , Hill N , Sura A , Ye J , Fisher T , Suen N , Zhang M , Cheng L , Pribluda A , Chen H , Yeh WC , Li Y , Baribault H , Fletcher RB . A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model. Respir Res 2024; 25(1): 153

[27] Wang F , Chen L , Kong D , Zhang X , Xia S , Liang B , Li Y , Zhou Y , Zhang Z , Shao J , Zheng S , Zhang F . Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex. Hepatology 2024; 79(3): 606–623

[28] Segerer S , Nelson PJ , Schlöndorff D . Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol 2000; 11(1): 152–176

[29] Li H . Update on the role of chemokines and chemokine receptors in liver fibrosis. J Gastrointestin Liver Dis 2023; 32(2): 241–256

[30] Vielhauer V , Berning E , Eis V , Kretzler M , Segerer S , Strutz F , Horuk R , Gröne HJ , Schlöndorff D , Anders HJ . CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome. Kidney Int 2004; 66(6): 2264–2278

[31] Seki E , De Minicis S , Gwak GY , Kluwe J , Inokuchi S , Bursill CA , Llovet JM , Brenner DA , Schwabe RF . CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest 2009; 119(7): 1858–1870

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