Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice
BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by elevated androgen levels and impaired follicular development. A hallmark of PCOS is the excessive proliferation of thecal cells (TCs), which are critical for androgen production. However, the molecular mechani...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1633254/full |
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| author | Man Luo Man Luo Xiaona Tian Li Li Guomei Zhang Wenzhi Liu Linlin Mei Haoran Li Xiaoyan You Dongmei Zhang Mengsi Zhou Mengsi Zhou Cheng Xiao Cheng Xiao Jianping Ye Jianping Ye Xiaofeng Yang Xiaofeng Yang |
| author_facet | Man Luo Man Luo Xiaona Tian Li Li Guomei Zhang Wenzhi Liu Linlin Mei Haoran Li Xiaoyan You Dongmei Zhang Mengsi Zhou Mengsi Zhou Cheng Xiao Cheng Xiao Jianping Ye Jianping Ye Xiaofeng Yang Xiaofeng Yang |
| author_sort | Man Luo |
| collection | DOAJ |
| description | BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by elevated androgen levels and impaired follicular development. A hallmark of PCOS is the excessive proliferation of thecal cells (TCs), which are critical for androgen production. However, the molecular mechanisms underlying this aberrant cellular expansion remain incompletely understood.MethodsA DHEA-induced mouse model was used to recapitulate the hormonal and ovarian features of human PCOS. Spatial transcriptomics was employed to profile gene expression in ovarian tissue at cellular resolution. Differential expression analysis, pathway enrichment, and spatial co-localization were performed to identify regulatory networks. Functional assays were conducted in cultured TCs using siRNA-mediated knockdown of target genes, and cell proliferation and cell cycle progression were evaluated using EdU incorporation and flow cytometry.ResultsSpatial transcriptomic profiling revealed widespread transcriptional changes in the ovaries of PCOS mice, including a marked expansion of a TCs subpopulation with high Lrp2 expression. This subset exhibited enhanced activity in genes involved in androgen synthesis and cell cycle regulation. A signaling axis comprising Inhba, Smad2, and E2f4 was identified as a key regulator of this proliferative response, with all three genes co-expressed in the affected regions. Knockdown of any component of this axis significantly suppressed TCs proliferation in vitro, with the greatest effect observed upon Inhba silencing.ConclusionThe Inhba/Smad2/E2f4 axis contributes to thecal cell hyperplasia and androgen excess in PCOS, and may serve as a mechanistic entry point for further investigation into the regulation of TCs proliferation in this disorder. |
| format | Article |
| id | doaj-art-b89a3fada3c94da4a16062d8bf086e42 |
| institution | DOAJ |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-b89a3fada3c94da4a16062d8bf086e422025-08-20T03:18:27ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-08-011310.3389/fcell.2025.16332541633254Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS miceMan Luo0Man Luo1Xiaona Tian2Li Li3Guomei Zhang4Wenzhi Liu5Linlin Mei6Haoran Li7Xiaoyan You8Dongmei Zhang9Mengsi Zhou10Mengsi Zhou11Cheng Xiao12Cheng Xiao13Jianping Ye14Jianping Ye15Xiaofeng Yang16Xiaofeng Yang17Department of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaZhengzhou Key Laboratory of Endocrine Metabolism and Immunity in Polycystic Ovary Syndrome, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaZhengzhou Key Laboratory of Endocrine Metabolism and Immunity in Polycystic Ovary Syndrome, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaInstitute of Muscle Biology and Growth, Research Institute for Farm Animal Biology (FBN), Dummerstorf, GermanyInstitute of Agricultural and Environmental Sciences, Rostock University, Rostock, GermanyInstitute of Trauma and Metabolism, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaDepartment of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaZhengzhou Key Laboratory of Endocrine Metabolism and Immunity in Polycystic Ovary Syndrome, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaBackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by elevated androgen levels and impaired follicular development. A hallmark of PCOS is the excessive proliferation of thecal cells (TCs), which are critical for androgen production. However, the molecular mechanisms underlying this aberrant cellular expansion remain incompletely understood.MethodsA DHEA-induced mouse model was used to recapitulate the hormonal and ovarian features of human PCOS. Spatial transcriptomics was employed to profile gene expression in ovarian tissue at cellular resolution. Differential expression analysis, pathway enrichment, and spatial co-localization were performed to identify regulatory networks. Functional assays were conducted in cultured TCs using siRNA-mediated knockdown of target genes, and cell proliferation and cell cycle progression were evaluated using EdU incorporation and flow cytometry.ResultsSpatial transcriptomic profiling revealed widespread transcriptional changes in the ovaries of PCOS mice, including a marked expansion of a TCs subpopulation with high Lrp2 expression. This subset exhibited enhanced activity in genes involved in androgen synthesis and cell cycle regulation. A signaling axis comprising Inhba, Smad2, and E2f4 was identified as a key regulator of this proliferative response, with all three genes co-expressed in the affected regions. Knockdown of any component of this axis significantly suppressed TCs proliferation in vitro, with the greatest effect observed upon Inhba silencing.ConclusionThe Inhba/Smad2/E2f4 axis contributes to thecal cell hyperplasia and androgen excess in PCOS, and may serve as a mechanistic entry point for further investigation into the regulation of TCs proliferation in this disorder.https://www.frontiersin.org/articles/10.3389/fcell.2025.1633254/fullpolycystic ovary syndromespatial transcriptomicthecal cellandrogenproliferation |
| spellingShingle | Man Luo Man Luo Xiaona Tian Li Li Guomei Zhang Wenzhi Liu Linlin Mei Haoran Li Xiaoyan You Dongmei Zhang Mengsi Zhou Mengsi Zhou Cheng Xiao Cheng Xiao Jianping Ye Jianping Ye Xiaofeng Yang Xiaofeng Yang Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice Frontiers in Cell and Developmental Biology polycystic ovary syndrome spatial transcriptomic thecal cell androgen proliferation |
| title | Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice |
| title_full | Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice |
| title_fullStr | Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice |
| title_full_unstemmed | Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice |
| title_short | Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice |
| title_sort | spatial transcriptomics reveals inhba smad2 e2f4 axis in lrp2high thecal cell proliferation in androgen induced pcos mice |
| topic | polycystic ovary syndrome spatial transcriptomic thecal cell androgen proliferation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1633254/full |
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