Microbial Metabolites Control Self-renewal and Precancerous Progression of Human Cervical Stem Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Mar 8

PMID 40057497

Authors

Jihyeon Myeong

Minho Lee

Bawool Lee

Joon Hyung Kim

Yeji Nam

Yeseul Choi

Jeongmin Kim

Se Young Jeon

Haewon Shim

Da-Ryung Jung

Youngjin Shin

Minsoo Jeong

Byungmoo Oh

Jaehun Jung

Christine S Kim

Hyung Soo Han

Jae-Ho Shin

Yoon Hee Lee

Nora Jee-Young Park

Gun Oh Chong

Youngtae Jeong

Affiliations

Soon will be listed here.

Abstract

Cervical cancer is the fourth most common female cancer, with the uterine ectocervix being the most commonly affected site. However, cervical stem cells, their differentiation, and their regulation remain poorly understood. Here, we report the isolation of a population enriched for human cervical stem cells and their regulatory mechanisms. Using single-cell RNA sequencing, we characterize the cellular heterogeneity of the human ectocervix and identify cluster-specific cell surface markers. By establishing normal and precancerous cervical organoids and an intralingual transplantation system, we show that ITGB4 and CD24 enable enrichment of human and murine ectocervical stem cells. We discover that Lactobacilli-derived lactic acid regulates cervical stem cells' self-renewal and early tumorigenesis through the PI3K-AKT pathway and YAP1. Finally, we show that D-lactic acid suppresses growth of normal and precancerous organoids, while L-lactic acid does not. Our findings reveal roles of human cervical stem cells and microbial metabolites in cervical health and diseases.

References

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Gao W, Weng J, Gao Y, Chen X . Comparison of the vaginal microbiota diversity of women with and without human papillomavirus infection: a cross-sectional study. BMC Infect Dis. 2013; 13:271. PMC: 3684509. DOI: 10.1186/1471-2334-13-271. View

Singh D, Vignat J, Lorenzoni V, Eslahi M, Ginsburg O, Lauby-Secretan B . Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. Lancet Glob Health. 2022; 11(2):e197-e206. PMC: 9848409. DOI: 10.1016/S2214-109X(22)00501-0. View

Ruff W, Greiling T, Kriegel M . Host-microbiota interactions in immune-mediated diseases. Nat Rev Microbiol. 2020; 18(9):521-538. DOI: 10.1038/s41579-020-0367-2. View

Gurung S, Deane J, Darzi S, Werkmeister J, Gargett C . In Vivo Survival of Human Endometrial Mesenchymal Stem Cells Transplanted Under the Kidney Capsule of Immunocompromised Mice. Stem Cells Dev. 2017; 27(1):35-43. DOI: 10.1089/scd.2017.0177. View

Wang K, Xu D, Wang B, Yan D, Lv Z, Su J . Inhibitory Effect of Vaginal Lactobacillus Supernatants on Cervical Cancer Cells. Probiotics Antimicrob Proteins. 2017; 10(2):236-242. DOI: 10.1007/s12602-017-9339-x. View

de Magalhaes C, Linhares I, Masullo L, Eleuterio R, Witkin S, Eleuterio Jr J . Comparative measurement of D- and L-lactic acid isomers in vaginal secretions: association with high-grade cervical squamous intraepithelial lesions. Arch Gynecol Obstet. 2021; 305(2):373-377. DOI: 10.1007/s00404-021-06258-6. View

Yanagi S, Kishimoto H, Kawahara K, Sasaki T, Sasaki M, Nishio M . Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest. 2007; 117(10):2929-40. PMC: 1994617. DOI: 10.1172/JCI31854. View

Rock J, Onaitis M, Rawlins E, Lu Y, Clark C, Xue Y . Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci U S A. 2009; 106(31):12771-5. PMC: 2714281. DOI: 10.1073/pnas.0906850106. View

10.

Brusselaers N, Shrestha S, van de Wijgert J, Verstraelen H . Vaginal dysbiosis and the risk of human papillomavirus and cervical cancer: systematic review and meta-analysis. Am J Obstet Gynecol. 2018; 221(1):9-18.e8. DOI: 10.1016/j.ajog.2018.12.011. View

11.

. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015; 517(7536):576-82. PMC: 4311405. DOI: 10.1038/nature14129. View

12.

Lee J, Lee S, Lee H, Song Y, Lee K, Han M . Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort. PLoS One. 2013; 8(5):e63514. PMC: 3661536. DOI: 10.1371/journal.pone.0063514. View

13.

Wang Y, Xu X, Maglic D, Dill M, Mojumdar K, Ng P . Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer. Cell Rep. 2018; 25(5):1304-1317.e5. PMC: 6326181. DOI: 10.1016/j.celrep.2018.10.001. View

14.

Zhang H, Pasolli H, Fuchs E . Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci U S A. 2011; 108(6):2270-5. PMC: 3038759. DOI: 10.1073/pnas.1019603108. View

15.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

16.

Sharma P, Kaur S, Kaur R, Kaur M, Kaur S . Proteinaceous Secretory Metabolites of Probiotic Human Commensal 20c, 12a and L12b as Antiproliferative Agents Against Cancer Cell Lines. Front Microbiol. 2018; 9:948. PMC: 5962654. DOI: 10.3389/fmicb.2018.00948. View

17.

Chan C, Gulati G, Sinha R, Tompkins J, Lopez M, Carter A . Identification of the Human Skeletal Stem Cell. Cell. 2018; 175(1):43-56.e21. PMC: 6400492. DOI: 10.1016/j.cell.2018.07.029. View

18.

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View

19.

Frazer I . Prevention of cervical cancer through papillomavirus vaccination. Nat Rev Immunol. 2004; 4(1):46-54. DOI: 10.1038/nri1260. View

20.

Regauer S, Reich O . The origin of Human Papillomavirus (HPV) - induced cervical squamous cancer. Curr Opin Virol. 2021; 51:111-118. DOI: 10.1016/j.coviro.2021.09.012. View