Basic Study
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World J Stem Cells. Jan 26, 2025; 17(1): 98349
Published online Jan 26, 2025. doi: 10.4252/wjsc.v17.i1.98349
Bone marrow mesenchymal stem cells promote uterine healing by activating the PI3K/AKT pathway and modulating inflammation in rat models
Jing Yang, Jun Yuan, Yan-Qing Wen, Li Wu, Jiu-Jiang Liao, Hong-Bo Qi
Jing Yang, Jun Yuan, Yan-Qing Wen, Li Wu, Jiu-Jiang Liao, Hong-Bo Qi, Women and Children’s Hospital of Chongqing Medical University, Chongqing 401147, China
Jing Yang, Jun Yuan, Yan-Qing Wen, Jiu-Jiang Liao, Hong-Bo Qi, Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China
Jing Yang, Obstetrics and Gynecology, Guizhou Provincial People’s Hospital, Guiyang 557300, Guizhou Province, China
Hong-Bo Qi, Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
Co-corresponding authors: Jiu-Jiang Liao and Hong-Bo Qi.
Author contributions: Yang J, Liao JJ, and Qi HB made substantial contributions to the conception and design of the study, drafting the article and critically revising it for important intellectual content; Yang J and Yuan J performed the experiments; Yang J, Wen YQ, and Wu L acquired and analyzed the data; All authors approved the final version for publication. Liao JJ and Qi HB contributed to the discussion of the data, funding acquisition and supervision; they are co-corresponding authors of this manuscript.
Supported by the National Natural Science Foundation of China, No. 82301919; China Postdoctoral Science Foundation, No. 2023M730441; Guizhou Provincial Science and Technology Projects, No. [2020]1Y149; Joint Funds of the National Natural Science Foundation of China, No. U21A20346; and the Key Research Program of Chongqing Science and Technology Bureau, No. CSTB2022TIAD-KPX0156.
Institutional animal care and use committee statement: This study and the experimental procedures were approved by the Guizhou Provincial People’s Hospital. All animal experiments were approved by the Animal Care and Use Committee of the Ethical Institution of the Guizhou Provincial People’s Hospital, ethics approval number: (2019)163.
Conflict-of-interest statement: 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 used and/or analyzed during the current study are available from the corresponding author upon 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: Hong-Bo Qi, MD, PhD, Professor, Women and Children’s Hospital of Chongqing Medical University, No. 120 Longshan Road, Yubei District, Chongqing 401147, China. qihongbo@cqmu.edu.cn
Received: July 2, 2024
Revised: October 2, 2024
Accepted: December 10, 2024
Published online: January 26, 2025
Processing time: 202 Days and 2.2 Hours
Abstract
BACKGROUND

Uterine injury can cause uterine scarring, leading to a series of complications that threaten women’s health. Uterine healing is a complex process, and there are currently no effective treatments. Although our previous studies have shown that bone marrow mesenchymal stem cells (BMSCs) promote uterine damage repair, the underlying mechanisms remain unclear. However, exploring the specific regulatory roles of BMSCs in uterine injury treatment is crucial for further understanding their functions and enhancing therapeutic efficacy.

AIM

To investigate the underlying mechanism by which BMSCs promote the process of uterine healing.

METHODS

In in vivo experiments, we established a model of full-thickness uterine injury and injected BMSCs into the uterine wound. Transcriptome sequencing was performed to determine the enrichment of differentially expressed genes at the wound site. In in vitro experiments, we isolated rat uterine smooth muscle cells (USMCs) and cocultured them with BMSCs to observe the interaction between BMSCs and USMCs in the microenvironment.

RESULTS

We found that the differentially expressed genes were mainly related to cell growth, tissue repair, and angiogenesis, while the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was highly enriched. Quantitative reverse-transcription polymerase chain reaction was used to validate differentially expressed genes, and the results demonstrated that BMSCs can upregulate genes related to regeneration and downregulate genes related to inflammation. Coculturing BMSCs promoted the migration and proliferation of USMCs, and the USMC microenvironment promoted the myogenic differentiation of BMSCs. Finally, we validated the PI3K/AKT pathway in tissues and cells and showed that BMSCs activate the PI3K/AKT pathway to promote the regeneration of uterine smooth muscle both in vivo and in vitro.

CONCLUSION

BMSCs upregulated uterine wound regeneration and anti-inflammatory factors and enhanced uterine smooth muscle proliferation through the PI3K/AKT pathway both in vivo and in vitro.

Keywords: Uterine injury; Bone marrow mesenchymal stem cells; Uterine smooth muscle cells; Phosphoinositide 3-kinase/protein kinase B pathway; Cell-cell interactions; Cell proliferation; Immune regulation; Wound regeneration

Core Tip: We identified differentially genes in uterine wound tissues through transcriptome sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that regeneration and anti-inflammatory factors were upregulated in bone mesenchymal stem cell (BMSCs) groups and that the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin pathway was highly enriched. This study also demonstrated that BMSCs significantly promoted the proliferation and migration of uterine smooth muscle cells (USMCs) and that USMCs enhanced the myogenic differentiation of BMSCs. In vivo and in vitro experiments demonstrate that BMSCs activate the phosphoinositide 3-kinase/protein kinase B pathway in wound tissues and USMCs.