Protein & Cell >

2024 , Vol. 15 >Issue 7: 530 - 546

DOI: https://doi.org/10.1093/procel/pwae012

Comprehensive transcriptional atlas of human adenomyosis deciphered by the integration of single-cell RNA-sequencing and spatial transcriptomics

  • Tao Chen 1,2 ,
  • Yiliang Xu 3 ,
  • Xiaocui Xu 2 ,
  • Jianzhang Wang 4 ,
  • Zhiruo Qiu 5 ,
  • Yayuan Yu 1 ,
  • Xiaohong Jiang 1 ,
  • Wanqi Shao 6 ,
  • Dandan Bai 2 ,
  • Mingzhu Wang 2 ,
  • Shuyan Mei 5 ,
  • Tao Cheng 5 ,
  • Li Wu , 7 ,
  • Shaorong Gao , 2 ,
  • Xuan Che , 1,5
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  • 1. Department of Obstetrics and Gynecology, Affiliated Women and Children Hospital of Jiaxing University, Jiaxing 314000, China
  • 2. Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
  • 3. Key Laboratory of Animal Bioengineering and Disease Prevention of Shandong Province, College of Animal Science and Technology, Shandong Agricultural University, Taian 271018, China
  • 4. Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310013, China
  • 5. Postgraduate training base Alliance of Wenzhou Medical University, Wenzhou Medical University, Wenzhou 325035, China
  • 6. Jiaxing University Master Degree Cultivation Base, Zhejiang Chinese Medical University, Hangzhou 310053, China
  • 7. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
14_wuli@tongji.edu.cn
gaoshaorong@tongji.edu.cn
chexuan@zjxu.edu.cn

Received date: 15 Dec 2023

Accepted date: 29 Feb 2024

Copyright

2024 The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.
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Abstract

Adenomyosis is a poorly understood gynecological disorder lacking effective treatments. Controversy persists regarding “invagination” and “metaplasia” theories. The endometrial-myometrial junction (EMJ) connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis, but its in-depth study is just beginning. Using single-cell RNA sequencing and spatial profiling, we mapped transcriptional alterations across eutopic endometrium, lesions, and EMJ. Within lesions, we identified unique epithelial (LGR5+) and invasive stromal (PKIB+) subpopulations, along with WFDC1+ progenitor cells, supporting a complex interplay between “invagination” and “metaplasia” theories of pathogenesis. Further, we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways. Cell-cell communication differed markedly between ectopic and eutopic endometrium, with aberrant signaling in lesions involving pleiotrophin, TWEAK, and WNT cascades. This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified, dysfunctional signaling, and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.

Key words： adenomyosis; single-cell RNA sequencing; spatial transcriptomics; endometrial-myometrial junction; progenitor cells

Cite this article

Tao Chen , Yiliang Xu , Xiaocui Xu , Jianzhang Wang , Zhiruo Qiu , Yayuan Yu , Xiaohong Jiang , Wanqi Shao , Dandan Bai , Mingzhu Wang , Shuyan Mei , Tao Cheng , Li Wu , Shaorong Gao , Xuan Che . Comprehensive transcriptional atlas of human adenomyosis deciphered by the integration of single-cell RNA-sequencing and spatial transcriptomics[J]. Protein & Cell, 2024 , 15(7) : 530 -546 . DOI: 10.1093/procel/pwae012

References

Publishing order | Descend order by publishing year | Descend order by cited within
1
Altmäe S, Koel M, Võsa U. Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers. Sci Rep2017; 7: 10077.

2
Athanasiadis EI, Botthof JG, Andres H. Single-cell RNA-sequencing uncovers transcriptional states and fate decisions in haematopoiesis. Nat Commun2017; 8: 2045.

3
Barker N, van Es JH, Kuipers J. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature2007; 449: 1003-1007.

4
Benagiano G, Brosens I. History of adenomyosis. Best Pract Res Clin Obstet Gynaecol2006; 20: 449-463.

5
Blache P, van de Wetering M, Duluc I. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol2004; 166: 37-47.

6
Bourdon M, Santulli P, Jeljeli M. Immunological changes associated with adenomyosis: a systematic review. Hum Reprod Update2021; 27: 108-129.

7
Brabletz T, Jung A, Dag S. beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol1999; 155: 1033-1038.

8
Chapron C, Vannuccini S, Santulli P. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update2020; 26: 392-411.

9
Chen Y, Zhu J, Chen L. SFRP4(+)IGFBP5(hi) NKT cells induced neural-like cell differentiation to contribute to adenomyosis pain. Front Immunol2022; 13: 945504.

10
Das A, Ash D, Fouda AY. Cysteine oxidation of copper transporter CTR1 drives VEGFR2 signalling and angiogenesis. Nat Cell Biol2022; 24: 35-50.

11
Dason ES, Chan C, Sobel M. Diagnosis and treatment of adenomyosis. CMAJ2021; 193: E242.

12
Denzer L, Muranyi W, Schroten H . 2023. The role of PLVAP in endothelial cells. Cell Tissue Res392: 393-412.

13
de Visser KE, Ciampricotti M, Michalak EM . Developmental stage-specific contribution of LGR5(+)cells to basal and luminal epithelial lineages in the postnatal mammary gland. J Pathol2012; 228: 300-309.

14
Donnez J, Donnez O, Dolmans MM. Introduction: uterine adenomyosis, another enigmatic disease of our time. Fertil Steril2018; 109: 369-370.

15
García-Solares J, Donnez J, Donnez O. Pathogenesis of uterine adenomyosis: invagination or metaplasia? Fertil Steril2018; 109: 371-379.

16
Guo SW. The pathogenesis of Adenomyosis vis-à-vis endometriosis. J Clin Med2020; 9: 485.

17
Harmsen MJ, Arduç A, Bleeker MCG. Increased angio-genesis and lymphangiogenesis in Adenomyosis visualized by multiplex immunohistochemistry. Int J Mol Sci2022; 23: 8434.

18
Huang H, Bhat A, Woodnutt G. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer2010; 10: 575-585.

19
Kho KA, Chen JS, Halvorson LM. Diagnosis, evaluation, and treatment of adenomyosis. JAMA2021; 326: 177-178.

20
Kobayashi H. Efficacy, adverse events, and challenges of dienogest in the management of symptomatic Adenomyosis: a comparison with different hormonal treatments. Gynecol Obstet Invest2023; 88: 71-80.

21
Kobayashi H, Kishi Y, Matsubara S. Mechanisms underlying adenomyosis-related fibrogenesis. Gynecol Obstet Invest2020; 85: 1-12.

22
Lai ZZ, Wang Y, Zhou WJ. Single-cell transcriptome profiling of the human endometrium of patients with recurrent implantation failure. Theranostics2022; 12: 6527-6547.

23
La Porta S, Roth L, Singhal M. Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis. J Clin Invest2018; 128: 834-845.

24
Lee HW, Xu Y, He L. Role of venous endothelial cells in developmental and pathologic angiogenesis. Circulation2021; 144: 1308-1322.

25
Leung C, Tan SH, Barker N. Recent advances in Lgr5(+) stem cell research. Trends Cell Biol2018; 28: 380-391.

26
Liu Z, Sun Z, Liu H. Single-cell transcriptomic analysis of eutopic endometrium and ectopic lesions of adenomyosis. Cell Biosci2021; 11: 51.

27
Liu Z, Liu J, Chen T. Wnt-TCF7-SOX9 axis promotes cholangiocarcinoma proliferation and pemigatinib resistance in a FGF7-FGFR2 autocrine pathway. Oncogene2022; 41: 2885-2896.

28
Lv F, Li X, Wang Y et al. MAGP1 maintains tumorigenicity and angiogenesis of laryngeal cancer by activating Wnt/β-catenin/MMP7 pathway. Carcinogenesis 2023;bgad003.

29
Martire FG, Lazzeri L, Conway F. Adolescence and endometriosis: symptoms, ultrasound signs and early diagnosis. Fertil Steril2020; 114: 1049-1057.

30
Moawad G, Youssef Y, Fruscalzo A. The present and the future of medical therapies for Adenomyosis: a narrative review. J Clin Med2023; 12: 6130.

31
Naftalin J, Jurkovic D. The endometrial-myometrial junction:a fresh look at a busy crossing. Ultrasound Obstet Gynecol2009; 34: 1-11.

32
Pados G, Gordts S, Sorrentino F. Adenomyosis and infertility: a literature review. Medicina (Kaunas)2023; 59: 1551.

33
Seishima R, Leung C, Yada S. Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development. Nat Commun2019; 10: 5378.

34
Shi Y, Ping YF, Zhou W. Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nat Commun2017; 8: 15080.

35
Shih AJ, Adelson RP, Vashistha H. Single-cell analysis of menstrual endometrial tissues defines phenotypes associated with endometriosis. BMC Med2022; 20: 315.

36
Signer RA, Magee JA, Salic A. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature2014; 509: 49-54.

37
Spears E, Neufeld KL. Novel double-negative feedback loop between adenomatous polyposis coli and Musashi1 in colon epithelia. J Biol Chem2011; 286: 4946-4950.

38
Stefater JA 3rd, Lewkowich I, Rao S. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature2011; 474: 511-515.

39
Stefater JA 3rd, Rao S, Bezold K. Macrophage WntCalcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair. Blood2013; 121: 2574-2578.

40
Stratopoulou CA, Donnez J, Dolmans MM. Origin and pathogenic mechanisms of uterine adenomyosis: what is known so far. Reprod Sci2021; 28: 2087-2097.

41
Tan Y, Flynn WF, Sivajothi S. Single-cell analysis of endometriosis reveals a coordinated transcriptional programme driving immunotolerance and angiogenesis across eutopic and ectopic tissues. Nat Cell Biol2022; 24: 1306-1318.

42
Tempest N, Baker AM, Wright NA. Does human endometrial LGR5 gene expression suggest the existence of another hormonally regulated epithelial stem cell niche? Hum Reprod2018; 33: 1052-1062.

43
Vannuccini S, Tosti C, Carmona F. Pathogenesis of adenomyosis: an update on molecular mechanisms. Reprod Biomed Online2017; 35: 592-601.

44
Wan R, Yang G, Liu Q. PKIB involved in the metastasis and survival of osteosarcoma. Front Oncol2022; 12: 965838.

45
Wang S, Li L, Cook C. A potential fate decision landscape of the TWEAK/Fn14 axis on stem and progenitor cells: a systematic review. Stem Cell Res Ther2022; 13: 270.

46
Xu P, Ding S, Zhu L. Elevated RON protein expression in endometriosis and disease-associated ovarian cancers. Arch Gynecol Obstet2017; 295: 631-639.

47
Yildiz S, Kinali M, Wei JJ. Adenomyosis: single-cell transcriptomic analysis reveals a paracrine mesenchymal-epithelial interaction involving the WNT/SFRP pathway. Fertil Steril2023; 119: 869-882.

48
Yu O, Schulze-Rath R, Grafton J. Adenomyosis incidence, prevalence and treatment: United States population-based study 2006-2015. Am J Obstet Gynecol2020; 223: 94.e91-94.e10.

49
Zhang X, Qi C, Lin J. Enhanced expressions of matrix metalloproteinase (MMP)-2 and -9 and vascular endothelial growth factors (VEGF) and increased microvascular density in the endometrial hyperplasia of women with anovulatory dysfunctional uterine bleeding. Fertil Steril2010; 93: 2362-2367.

50
Zhang JB, Song W, Wang YY. Study on correlation between PKIB and pAkt expression in breast cancer tissues. Eur Rev Med Pharmacol Sci 2017; 21: 1264-1269.

51
Zhang J, Cai H, Sun L. LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients. J Exp Clin Cancer Res2018; 37: 225.

52
Zhang M, Bazot M, Tsatoumas M. MRI of adenomyosis:where are we today? Can Assoc Radiol J2023; 74: 58-68.

53
Zhu S, Ye L, Bennett S. Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer. Cell Biochem Funct2021; 39: 588-595.

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