Key Takeaways & Executive Findings
- •• hUC-MSCs and their EVs show therapeutic potential for reproductive disorders by reducing oxidative stress, autophagy, and ferroptosis while promoting anti-inflammatory factors and vascular remodeling. • EVs offer advantages over hUC-MSCs, including lower tumorigenicity and higher infusion efficiency, making them a promising alternative for cell-free therapy. • The review highlights the mechanisms of hUC-MSC/EV action in treating female and male infertility, emphasizing their role in endometrial repair and fertility restoration. • Future research should focus on optimizing EV production and standardization to translate these findings into clinical applications for reproductive medicine.
Abstract
Reproductive system disorders significantly contribute to infertility, and traditional or conventional treatments often have limited efficacy in addressing this issue. In recent years, stem cell therapy has emerged as an alternative therapeutic strategy owing to its various advantages. Human umbilical cord mesenchymal stem cells (hUC-MSCs) are pivotal in tissue repair owing to their robust proliferative capacity, potent immunomodulatory effects, low immunogenicity, and paracrine actions. Extracellular vesicles (EVs), the primary mediators of paracrine functions, exhibit therapeutic effects similar to those of hUC-MSCs. Consequently, numerous researchers have investigated the application of hUC-MSCs and their EVs in treating reproductive disorders. These cells have the potential to restore fertility by mitigating oxidative stress, excessive autophagy, and ferroptosis in tissues, while promoting the expression of anti-inflammatory factors and vascular remodeling. However, hUC-MSCs present significant limitations compared to EVs, including higher tumorigenicity and low infusion efficiency. Consequently, EVs may emerge as the primary alternative therapy, while hUC-MSCs hold promise as a therapeutic option with potential applications in regenerative medicine.
1. Introduction
In recent years, reproductive system disorders have affected the health and well-being of millions of couples worldwide [1]. In the female reproductive system, the ovaries and uterus play a crucial role in both natural conception and in vitro fertilization [2]. Healthy ovaries are essential for ensuring oocyte quality and maturation in females. Once the oocytes merge with sperm to form zygotes, they develop in the fallopian tubes before being implanted into the uterus; consequently, any phenotypic abnormalities or functional disorders in these structures can lead to infertility [3, 4].
Stem cells and extracellular vesicles (EVs) are currently utilized in various areas of disease treatment. For instance, stem cells can address acute myocardial infarction by releasing biological factors, whereas mesenchymal stem cell (MSCs)-derived EVs can significantly inhibit tumor cell growth [5–7]. Moreover, enhancing the effectiveness of stem cells in disease treatment has become an important area of interest. For example, the use of hematopoietic stem cells that express tumor-associated antigen-specific T-cell receptors or chimeric antigen receptors is being explored for treating acute myeloid leukemia [8].
Stem cells are a population of cells with self-renewal and multilineage differentiation potential that can be differentiated into at least one type of highly differentiated daughter cell in a controlled manner [9]. These cells are typically categorized as embryonic stem cells, adult stem cells, and induced pluripotent stem cells. However, the ethical controversies associated with embryonic stem cell research and clinical applications, coupled with the inefficiency and teratogenic potential of induced pluripotent stem cells, present significant challenges [10, 11]. Mesoderm-derived MSCs have been widely used in the treatment of various diseases because of their strong proliferation ability, pluripotency, genomic stability in vitro, and lack of ethical issues [11, 12]. (As shown in Fig. 1)
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Xin Guo, Bingchun Liu, Peixin Xu, Hong Chen, Jing Gao, Dongmei Yao, Xin Li, Yurong Wang, Tong Wang, Hongrui Yao, Shuwei Qiao, Jile Huge, Jianlong Yuan (2026). Research on the mechanism of human umbilical cord mesenchymal stem cells and their extracellular vesicles in the treatment of common reproductive diseases. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04773-w
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Frequently Asked Questions
What are human umbilical cord mesenchymal stem cells (hUC-MSCs)?
hUC-MSCs are multipotent stem cells derived from the umbilical cord, known for their robust proliferative capacity, immunomodulatory effects, low immunogenicity, and paracrine actions, making them promising for tissue repair and regenerative medicine.
How do extracellular vesicles (EVs) from hUC-MSCs help in treating reproductive diseases?
EVs derived from hUC-MSCs carry bioactive molecules that mitigate oxidative stress, excessive autophagy, and ferroptosis, while promoting anti-inflammatory factors and vascular remodeling, thereby restoring fertility in reproductive disorders.
What are the advantages of using EVs over hUC-MSCs for therapy?
EVs offer lower tumorigenicity and higher infusion efficiency compared to hUC-MSCs, making them a safer and more effective alternative for cell-free therapy in reproductive diseases.
Which reproductive conditions can be treated with hUC-MSCs and their EVs?
These therapies have shown potential in treating female infertility conditions like endometrial injury and ovarian dysfunction, as well as male infertility, by promoting tissue repair and reducing inflammation.
What is the current status of hUC-MSC/EV therapy in clinical practice?
While preclinical studies are promising, clinical applications are still in early stages. Further research is needed to standardize EV production, determine optimal dosages, and conduct large-scale clinical trials to establish safety and efficacy.
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