Letter to the Editor
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Apr 26, 2025; 17(4): 102482
Published online Apr 26, 2025. doi: 10.4252/wjsc.v17.i4.102482
Hypoxic endometrial epithelial cell-derived microRNAs effectively regulate the regenerative properties of mesenchymal stromal cells
Panagiotis Mallis
Panagiotis Mallis, Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Attikí, Greece
Author contributions: Mallis P wrote and revised the manuscript.
Conflict-of-interest statement: The author reports no relevant conflicts of interest for this article.
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: Panagiotis Mallis, PhD, Postdoctoral Fellow, Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, Athens 11527, Attikí, Greece. pmallis@bioacademy.gr
Received: October 21, 2024
Revised: February 6, 2025
Accepted: March 5, 2025
Published online: April 26, 2025
Processing time: 186 Days and 6.8 Hours
Abstract

Endometrial thickness plays an important role in successful embryo implantation and normal pregnancy achievement. However, a thin endometrial layer (≤ 7 mm) may have a significant effect on microenvironment tolerance, which is further related to successful embryo implantation or conception, either naturally or after assisted reproductive technology. Moreover, this microenvironment tolerance shift induces hypoxic damage to endometrial epithelial cells (EECs), which results in altered signaling biomolecule secretion, including exosome content. In the context of endometrium regeneration, mesenchymal stromal cells (MSCs) and umbilical cord (UC)-derived stem cells have been applied in clinical trials with promising results. It has been recently shown that exosomes derived from hypoxic damaged EECs directly contribute to the increased migratory and regenerative abilities of UCs and MSCs. Specifically, microRNAs in exosomes secreted by the hypoxic damaged EECs, such as miR-214-5p and miR-21-5p, play a crucial role in the migratory capacity and differentiation ability of MSCs to EECs mediated through the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Taking into consideration the above information, UC-MSCs may be considered as a modern intervention for endometrial regeneration.

Keywords: MicroRNAs; Mesenchymal stromal cells; Endometrial tissue; Wound healing; Tissue regeneration; MiR-214-5p; MiR-21-5p

Core Tip: Endometrial tissue damage is the primary reason for unsuccessful embryo implantation. Hypoxic damaged endometrial epithelial cells can secrete miRNAs through exosomes, which can efficiently regulate endometrial microenvironment homeostasis. Specifically, miR-21-5p and miR-214-5p can regulate the migration, wound healing and differentiation of umbilical cord-derived mesenchymal stromal cells. Therefore, the latter favors endometrial tissue regeneration. By understanding the primary endometrial defect, alternative therapeutic protocols such as advanced cellular therapies may be used to restore women’s fertility.