Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 28, 2025; 31(24): 104437
Published online Jun 28, 2025. doi: 10.3748/wjg.v31.i24.104437
miR-10a-5p and miR-10b-5p restore colonic motility in aged mice
Gain Baek, Rajan Singh, Se Eun Ha, Hayeong Cho, Sesh Padmanabhan, Vachan Vishwanath, Min Seob Kim, Dahyun Seon, Jisong You, Moon Young Lee, Seungil Ro
Gain Baek, Rajan Singh, Se Eun Ha, Hayeong Cho, Sesh Padmanabhan, Vachan Vishwanath, Seungil Ro, Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, United States
Min Seob Kim, Dahyun Seon, Jisong You, Moon Young Lee, Department of Physiology, Wonkwang University, Iksan 54538, South Korea
Co-first authors: Gain Baek and Rajan Singh.
Author contributions: Baek G, Singh R, Ha SE, and Ro S conception or design; Baek G, Singh R, Ha SE, Cho H, Padmanabhan S, Vishwanath V, Kim MS, Seon D, You J and Lee MY analysis, or interpretation of data; Baek G, Singh R and Ha SE drafting the work; Ro S revising; All authors have read and agreed to the published version of the manuscript.
Supported by National Institutes of Health Grants, No. R01DK103055 (to Ro S); RosVivo Therapeutics, No. AWD-01-00003158 (to Ro S); and the National Research Foundation of Korea Grant Funded by the Korean Government (MSIT), No. NRF-2021R1C1C2006743 (to Kim MS) and No. NRF-2021R1A2C1095311 (to Lee MY).
Institutional review board statement: Informed consent was obtained from all participants, and the study protocol was approved by the Wonkwang University Institutional Review Board, No. WKIRB-201906-BR-046.
Institutional animal care and use committee statement: All processes involving animal subjects were approved by the Institutional Animal Care and Use Committee at University of Nevada, Reno, which is fully accredited by the American Association for Accreditation of Laboratory Animal Care International, No. 20-05-1007-1.
Conflict-of-interest statement: This author discloses the following: Ro S and the University of Nevada Reno Office of Technology Transfer (serial No. 62/837,988, filed 24 April 2019) have published a PCT International Patent WO/2020/219872 entitled “Methods and compositions of miR-10 mimics and targets thereof”. Ro S is an employee and a member of the board of directors of RosVivo Therapeutics. Ha SE and Singh R are members of the board of directors of RosVivo Therapeutics. The remaining authors disclose no conflicts.
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: No additional data are available.
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: Seungil Ro, PhD, Professor, Department of Physiology and Cell Biology, University of Nevada School of Medicine, Center for Molecular Medicine L-207E, 1664 North Virginia Street, Reno, NV 89557, United States. sro@med.unr.edu
Revised: March 18, 2025
Accepted: June 3, 2025
Published online: June 28, 2025
Processing time: 188 Days and 12.6 Hours
Abstract
BACKGROUND

We previously identified miR-10b-5p as a key regulator of gastrointestinal (GI) motility through its essential role in the development and function of interstitial cells of Cajal (ICC), the pacemaker cells of the gut. Loss of miR-10b-5p in ICC impairs intestinal motility and contributes to constipation, a common condition in the elderly. Notably, miR-10b-5p is co-expressed with its paralog, miR-10a-5p, in ICC.

AIM

To investigate the roles of miR-10a-5p and miR-10b-5p in age-associated intestinal dysmotility and assess the therapeutic potential of restoring their expression.

METHODS

We employed aged mice, mir-10a and mir-10b single and double knockout (KO) models, and human plasma and colon samples across age groups. GI and colonic transit, ICC network integrity, and expression levels of miR-10a/b-5p were evaluated. Additionally, we tested whether treatment with their microRNA mimics could restore GI motility in aged mice.

RESULTS

Aged mice exhibited delayed GI and colonic transit, reduced fecal output, and diminished expression of miR-10a-5p and miR-10b-5p, which peaked during late embryonic and early postnatal stages and declined with age. This decline paralleled ICC network deterioration in the colon. All KO models exhibited impaired motility and ICC loss, with mir-10a KO mice displaying more severe phenotypes than mir-10b KO mice. Double KO mice demonstrated growth retardation and reduced survival, with homozygous mutants living only up to 3 months. Treatment of aged mice with miR-10a-5p and miR-10b-5p mimics encapsulated in jetPEI significantly improved GI and colonic motility. Successful delivery to the gut, including the colon, was confirmed. In human samples, both miR-10a/b-5p and KIT expression decreased with age.

CONCLUSION

miR-10a-5p and miR-10b-5p are essential for ICC maintenance and colonic motility, and their age-related decline contributes to GI dysmotility in both mice and humans. Restoring their levels offers a promising therapeutic strategy for treating age-related constipation and other motility disorders.

Keywords: MicroRNAs; Aged mice; Gastrointestinal dysmotility; Constipation; Interstitial cells of Cajal

Core Tip: Gastrointestinal (GI) dysmotility is strongly associated with aging, driven by functional changes in the gut. We previously identified miR-10b-5p as a key regulator of GI motility disorders. However, the specific roles of miR-10a-5p and miR-10b-5p in age-related GI dysmotility remain unexplored. This study presents compelling evidence supporting the miR-10a-5p and miR-10b-5p as critical regulators of interstitial cells of Cajal growth and function, playing essential roles in maintaining GI motility in aged mice and humans. Restoration of these microRNAs through miR-10a-5p and miR-10b-5p mimics in aged mice effectively alleviated GI dysmotility, particularly constipation, offering a promising therapeutic strategy for age-related GI motility disorders.