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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Paneth cells inhibit intestinal stem cell proliferation through the bone morphogenic protein 7 pathway under rotavirus-mediated intestinal injury
Xiang-Yi Bu, Hao-Yuan Tan, An-Min Wang, Ming-Tong Wei, Sophie Pan, Juan-Zi Gao, Yong-Hai Li, Gui-Xiang Qian, Zi-Han Chen, Chao Ye, Wei-Dong Jia
Xiang-Yi Bu, Juan-Zi Gao, Zi-Han Chen, Wei-Dong Jia, Department of Hepatic Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Hao-Yuan Tan, An-Min Wang, Chao Ye, Department of Digestive Disease, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Hao-Yuan Tan, An-Min Wang, Chao Ye, Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Ming-Tong Wei, Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
Sophie Pan, Department of Life Sciences, University of California, Los Alamitos, CA 90025, United States
Yong-Hai Li, Gui-Xiang Qian, Hefei First People’s Hospital, The Third Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
Co-first authors: Xiang-Yi Bu and Hao-Yuan Tan.
Co-corresponding authors: Chao Ye and Wei-Dong Jia.
Author contributions: Bu XY and Tan HY administered the project and made equal contributions to this manuscript as co-first authors; Bu XY, Tan HY, Wang AM, Wei MT, and Qian GX performed data curation and formal analysis; Bu XY and Wei MT conducted the investigation; Bu XY drafted the original manuscript; Tan HY, Wei MT, Pan S, Gao JZ, Li YH, Chen ZH, and Ye C reviewed and edited the manuscript; Ye C and Jia WD supervised the study, conceptualized the research and made equal contributions to this manuscript as co-corresponding authors. All authors have read and approved the final manuscript.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Ethics Committee of the Institute of Health and Medicine, Hefei Comprehensive National Science Center (No. IHM-AP-2024-098-R1).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets and code used during the current study are available from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Wei-Dong Jia, MD, PhD, Professor, Department of Hepatic Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei 230001, Anhui Province, China.
jwd1968@ustc.edu.cn
Received: March 14, 2025
Revised: May 5, 2025
Accepted: June 13, 2025
Published online: July 14, 2025
Processing time: 119 Days and 15.3 Hours
BACKGROUND
Rotavirus (RV), a primary cause of diarrhea-related mortality in 2021, has been shown to damage intestinal epithelial cells while upregulating intestinal stem cells (ISCs) activities. ISCs within the crypt niche drive the continuous self-renewal of intestinal epithelium, preserving its barrier functions. Paneth cells secrete antimicrobial peptide and signaling molecules within the intestine crypt, thereby playing a crucial role in intestinal immune defense and providing ISCs functional support. However, the regulatory function of Paneth cells under pathological conditions, such as RV infection, remains unclear.
AIM
To determine the impact of RV infection on Paneth cells and how Paneth cells regulate ISCs during intestinal injury repair.
METHODS
We constructed a reference genome for the RV enteric cytopathogenic human orphan virus strain and reanalyzed published single-cell RNA sequencing data to investigate Paneth cell responses to RV-induced intestinal injury. We derived Paneth-ISC communication networks using CellChat, tracked ISC differentiation with pseudotime analysis, and validated our findings in leucine-rich repeat-containing G protein-coupled receptor 5-enhanced green fluorescent protein-internal ribosomal entry site-Cre recombinase estrogen receptor variant 2 mice and organoids via immunofluorescence, flow cytometry, and reverse transcription quantitative polymerase chain reaction.
RESULTS
We found that RV directly infects Paneth cells, leading to a reduction in mature Paneth cells and an increase in kallikrein 1-high immature Paneth cells. Paneth-ISC communication was significantly enhanced. In particular, the bone morphogenic protein 7 (BMP7)-activin A receptor type 2B/BMP receptor type 1A-Smad pathway was upregulated post-infection, suggesting that Paneth cells suppress excessive ISC proliferation. Functional validation confirmed activation of this pathway.
CONCLUSION
Paneth cells regulate ISC proliferation during RV infection by activating BMP7 signaling, limiting excessive stem cell expansion and preserving crypt homeostasis for effective epithelial repair.
Core Tip: This study uncovers a novel regulatory role of Paneth cells in intestinal stem cell (ISC) homeostasis during rotavirus infection. While Paneth cells are known for supporting ISCs, we demonstrate that rotavirus directly infects Paneth cells, resulting in a loss of mature Paneth cells. Paneth-ISC communication is significantly enhanced post-infection, with upregulation of the bone morphogenic protein 7 (BMP7)-activin A receptor type 2B/BMP receptor type 1A-Smad pathway, which limits excessive ISC proliferation. These findings provide new insights into crypt homeostasis and suggest BMP7 signaling as a potential target for intestinal repair in viral infections.
