Microbial metabolites control self-renewal and precancerous progression of human cervical stem cells
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.
Authors
- Jae‐Ho Shin (ORCID: https://orcid.org/0000-0001-6450-9787)
- Yeseul Choi (ORCID: https://orcid.org/0000-0001-7982-3736)
- Minsoo Jeong (ORCID: https://orcid.org/0000-0001-8797-8738)
- Youngtae Jeong (ORCID: https://orcid.org/0000-0001-6269-8190)
- Da-Ryung Jung
- Youngjin Shin (ORCID: https://orcid.org/0000-0003-1373-7557)
- Christine S. Kim (ORCID: https://orcid.org/0000-0001-7512-7960)
- Jeongmin Kim
- Gun Oh Chong (ORCID: https://orcid.org/0000-0003-4887-4017)
- Hyunyoung Shim (ORCID: https://orcid.org/0009-0002-5644-0067)
- Jihyeon Myeong (ORCID: https://orcid.org/0000-0001-5760-4743)
- Byungmoo Oh (ORCID: https://orcid.org/0009-0009-1805-3913)
- Minho Lee (ORCID: https://orcid.org/0000-0002-0168-9546)
- Ji Young Park (ORCID: https://orcid.org/0000-0002-1857-813X)
- Hyung Soo Han (ORCID: https://orcid.org/0000-0001-7200-0921)
- Jaehun Jung (ORCID: https://orcid.org/0000-0003-3422-1744)
- Se Young Jeon
- Joon Hyung Kim
- Yun Kwon Nam
- Yoon Hee Lee
- B.J. Lee
Institutions
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- Dongguk University (KR)
- Kyungpook National University Hospital (KR)
- Kyungpook National University (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-08
- DOI
- https://doi.org/10.1038/s41467-025-57323-6
- Citations
- 7
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Ministry of Education
- Ministry of Health and Welfare
- Korea Health Industry Development Institute
- National Research Foundation of Korea
- Institute for Basic Science