Ma BD, Zhang SJ, Shao YM, Jin RR, Sun L, Lv PJ, Yue H, Hu SK, Ma XW. Erythropoietin-overexpressing mesenchymal stem cells accelerate diabetic wound healing via steroid signaling pathway modulation. World J Stem Cells 2026; 18(5): 116280 [DOI: 10.4252/wjsc.v18.i5.116280]
Corresponding Author of This Article
Xi-Wen Ma, MD, Professor, Department of Geriatric, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 16 Tongbai North Road, Zhongyuan District, Zhengzhou 450007, Henan Province, China. maxiwen@zzu.edu.cn
Research Domain of This Article
Cell & Tissue Engineering
Article-Type of This Article
research-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Bao-Dong Ma, Shu-Juan Zhang, Yi-Ming Shao, Ran-Ran Jin, Lei Sun, Peng-Ju Lv, Han Yue, Shou-Kui Hu, Xi-Wen Ma
Bao-Dong Ma, Yi-Ming Shao, Ran-Ran Jin, Lei Sun, Peng-Ju Lv, Han Yue, Cell Research and Translational Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, Henan Province, China
Shu-Juan Zhang, Shou-Kui Hu, Department of Laboratory Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, Henan Province, China
Xi-Wen Ma, Department of Geriatric, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, Henan Province, China
Author contributions: Ma BD and Zhang SJ contributed to the study design, data analysis, and manuscript writing, they contributed equally to this manuscript and are co-first authors; Ma BD and Shao YM were responsible for funding acquisition; Shao YM performed data analysis and bioinformatics analysis; Jin RR and Sun L conducted cell experiments; Lv PJ carried out animal experiments; Yue H, Hu SK, and Ma XW were involved in project design, data interpretation, and manuscript review.
Supported by the Science and Technology Project of Henan Province, No. 242102310112 and No. LHGJ20230786; and the Incubation Project of Advanced Medical Research Center, No. XJYXZX2021007.
Institutional review board statement: The study protocol for the collection and use of human umbilical cord-derived mesenchymal stem cells was reviewed and approved by the Ethics Committee of Zhengzhou Central Hospital Affiliated to Zhengzhou University (approval No. 2024-004). Written informed consent was obtained from all tissue donors or their legal guardians prior to sample collection, in accordance with the Declaration of Helsinki.
Institutional animal care and use committee statement: All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. ZZU-LAC0241220[023]. All experiments were conducted in accordance with institutional guidelines and the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and all efforts were made to minimize animal suffering and reduce the number of animals used.
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 original contributions presented in the study are included in the article (Supplementary material). Further inquiries can be directed to the corresponding author.
Corresponding author: Xi-Wen Ma, MD, Professor, Department of Geriatric, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 16 Tongbai North Road, Zhongyuan District, Zhengzhou 450007, Henan Province, China. maxiwen@zzu.edu.cn
Received: November 7, 2025 Revised: December 1, 2025 Accepted: February 24, 2026 Published online: May 26, 2026 Processing time: 199 Days and 21.5 Hours
Abstract
BACKGROUND
Chronic non-healing diabetic wounds are driven by persistent inflammation, impaired fibroblast function, and defective neovascularization. Mesenchymal stem cell (MSC)-based therapies show promise, but their efficacy is limited by suboptimal paracrine and immunomodulatory activity.
AIM
To determine whether erythropoietin-overexpressing MSCs (EPO-MSCs) enhance diabetic wound healing and to delineate the underlying immune mechanisms, with particular focus on serum amyloid A3-positive (Saa3+) macrophages and C-C motif chemokine ligand (CCL)-centered cell-cell communication.
METHODS
Human umbilical cord-derived MSCs were transduced with an EPO-expressing lentiviral vector and compared with negative control MSCs (NC-MSCs). Fibroblast migration was evaluated in vitro by scratch assays. A full-thickness excisional wound model was established in db/db mice, which received local injections of phosphate buffered saline, NC-MSCs, or EPO-MSCs. Wound closure, re-epithelialization, and collagen deposition were assessed histologically. Bulk transcriptomic and proteomic analyses of wound tissues were performed to identify altered pathways, and single-cell RNA sequencing with cell-cell communication analysis was used to characterize immune cell subsets and intercellular signaling.
RESULTS
EPO-MSCs retained typical MSCs surface markers and tri-lineage differentiation while secreting higher levels of EPO. Compared with NC-MSCs, EPO-MSCs significantly enhanced fibroblast migration in vitro and accelerated wound closure, increased epidermal thickness, and improved collagen organization in db/db mice. Multi-omics analyses indicated enrichment of pathways related to cell migration, angiogenesis, and inflammatory regulation. Single-cell RNA sequencing revealed an increased proportion of Saa3+ macrophages with an M2-like reparative phenotype in EPO-MSCs-treated wounds. These Saa3+ macrophages showed transcriptional signatures associated with neutrophil chemotaxis and angiogenesis, and communication analysis highlighted a strengthened CCL-C-C motif chemokine receptor signaling axis between Saa3+ macrophages and neutrophils.
CONCLUSION
EPO engineering augments the pro-regenerative and immunomodulatory functions of MSCs, promoting expansion of Saa3+ macrophages and CCL-centric crosstalk with neutrophils to accelerate diabetic wound repair. EPO-MSCs therefore represent a promising, mechanism-based cell therapy candidate for refractory diabetic wounds.
Core Tip: This study shows that erythropoietin-overexpressing mesenchymal stem cells (EPO-MSCs) accelerate diabetic wound repair by enhancing fibroblast migration, angiogenesis, and macrophage polarization. Integrated transcriptomic, proteomic, and single-cell analyses identify serum amyloid A3-positive reparative macrophages and C-C motif chemokine ligand-centered macrophage-neutrophil crosstalk as key immune nodes modulated by EPO-MSCs, alongside changes in steroid-related pathways. These mechanistic insights suggest that gene-engineered mesenchymal stem cells can overcome the chronic inflammatory microenvironment of diabetic wounds and provide a rationale for future dose optimization, safety evaluation, and early-phase clinical trials of EPO-MSCs therapy.
