Mesenchymal stem cells: Guardians of women's health

Changzhong Li conceived the work. Guanwen Gao wrote and drafted the manuscript. Li Li, Changling Li, Degao Liu, and Yunfei Wang discussed and edited the manuscript. All authors read and approved the final version of the manuscript.

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This work was supported by the China Shenzhen High-level Hospital Construction Fund ( YBH2019-260 ), the China Shenzhen Key Medical Discipline Construction Fund (No. SZXK027 ), the Sanming Project of Medicine in China Shenzhen (No. SZSM202011016 ), and the General Project of China Shenzhen Science and Technology Innovation Commission (No. JCYJ20220531094012027 ).

Pelvic floor dysfunction (PFD) refers to a group of diseases in which pelvic floor tissue is weakened due to injury, degeneration or other factors, leading to a decrease in pelvic floor support or pelvic floor muscle function, resulting in pelvic organ displacement and pelvic organ functional abnormalities. PFD is a common and frequently occurring condition in women of middle age and older. Pelvic organ prolapse, difficulty urinating and defecating, pelvic pain, stress urinary incontinence (SUI) and sexual dysfunction may occur in women with PFD [ 109 ], seriously affecting the normal social activities of patients and increasing their psychological stress. Research on the application of MSCs in the field of pelvic floor gynecology is lacking, and there is currently no effective method for stimulating the homing of MSCs in vivo in order to improve PFD. MSCs are safe for the treatment of pelvic diseases [ 110 ], and MSC-based treatment of SUI is a new method [ 111 ]. A new injectable and self-healing hydrogel derived from beta-chitin has been developed by scientists. It promotes MSC homing in vivo, thereby improving the local microenvironment, increasing collagen deposition, repairing periurethral tissue, and ultimately improving SUI [ 34 ] ( Table 1 ). This treatment may be an effective nonsurgical therapy for the prevention and treatment of SUI. Regarding surgical treatment, sling implantation is an important procedure for SUI treatment [ 112 , 113 ]. Several studies have reported that ADMSCs can be seeded on polyglycolic acid (PGA) fibers and cultured for 4 weeks to form tissue-engineered slings. Two months following the implantation of the sling into the SUI rat model, the mean leak point pressure (LPP) increased significantly [ 114 ] ( Fig. 2 c). The results of this study indicate that ADMSCs may be a promising novel cell source for tissue sling engineering. Furthermore, ADMSCs have the potential to enhance the therapeutic outcomes of SUI patients [ 115 ]. Nerve damage is a recognized cause of PFD [ 116 ]. The ability of MSC transplantation to repair pelvic floor nerve injury is good, and MSC-loaded gelatin scaffolds are more effective because they may promote and enhance nerve repair at an early stage [ 35 ] ( Table 1 ). Other studies have shown that MSCs and their secreted factors, such as brain-derived neurotrophic factor, improve regenerative capacity in animal models of neuromuscular injury [ 117 , 118 ]. These observations are expected to lead to a new type of treatment for postpartum pelvic neuromuscular injury.

With the deepening of research on MSCs, their functional value in gynecology and obstetrics diseases will gradually emerge. However, what we know is only a small part of the whole. Further research on the underlying mechanism of action is still needed, and resolving these controversial issues is needed to safely extend the use of MSCs from the laboratory to the clinic. We believe that with the continuous efforts of scientists and clinicians, there will be more MSC-based applications in clinical treatment and that more patients will benefit from these methods.

In 1991, scientists isolated MSCs, referred to as "fibroblast-like cells", from umbilical cord-derived Wharton's jelly and cultured them [ 1 ]. MSCs are stem cells with multidirectional differentiation potential that can differentiate into a wide range of cell types [ 2 ]. It was first demonstrated in 1999 that MSCs have the ability to differentiate into adipocytes, bone cells or chondrocytes in vitro. These findings have motivated scientists to study MSCs with the expectation that MSCs will play a significant role in the field of regenerative medicine [ 3 ]. MSCs can be transplanted into different people without fear of rejection because of their potent immunosuppressive function, thus preventing adverse reactions by the immune system [ 4 ]. MSCs can comprehensively repair damaged cells in the human body at the cellular level; these cells have not only regenerative and reparative effects on tissue cells but also powerful immunomodulatory functions [ 5 ]. These functions present a novel approach to cell regeneration therapy for challenging obstetrics and gynecologic diseases, such as ovarian, endometrial and pelvic dysfunction. It is believed that with in-depth research on MSCs, these cells will play a greater role in disease treatment and women's health in the future.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Although MSCs have shown great potential in the treatment of many diseases, their use in cancer therapy remains controversial [ 119 ]. Several studies have reported that MSCs may play a role in promoting ovarian cancer cell proliferation, metastasis and invasion. For example, one study revealed that MSCs isolated from the greater omentum promote the growth and metastasis of ovarian cancer cells [ 120 ]. Exosomes secreted into ascites have been demonstrated to promote the growth and metastasis of epithelial ovarian cancer [ 121 ]. ADMSCs increase the proliferation of ovarian cancer cells by upregulating the expression of paired box 8 in ovarian cancer cells and maintaining the stability of the PDZ-binding motif (TAZ). This finding suggests that PAX8 may be involved in regulating cancer progression [ 122 , 123 ]. Other studies have shown that MSCs in the ovarian cancer microenvironment can promote epithelial–mesenchymal transition in ovarian cancer cells through the secretion of IL-6 so that ovarian cancer cells can take on the characteristics of MSCs and increase the secretion of matrix metalloproteinases, thus promoting the invasion and metastasis of ovarian cancer cells [ 124 ]. Cancer-associated MSCs can promote ovarian cancer stem cell resistance to chemotherapy through platelet-derived growth factor (PDGF) signaling. PDGF-BB/PDGF-β is an important signaling pathway between cancer-associated MSCs and cancer stem-like cells in ovarian cancer [ [125] , [126] , [127] ]. These findings have implications for the development of specific ovarian cancer prevention therapies in the future. In the treatment of endometrial cancer, a small number of BM-MSCs in the blood circulation can be recruited and can infiltrate the lesion site, leading to the occurrence of deep infiltrating endometriosis [ 128 ]. It has also been reported that the proliferation of endometrial stromal cells increases after BM-MSCs are cocultured with endometriosis cell lines in vitro [ 129 ]. These findings suggest that MSCs may contribute to the growth of endometriotic lesions. Stem cell-derived nutritional factors can induce the proliferation of endometrial cells, leading to the occurrence and development of endometriosis. Targeted blockade of specific signaling molecules secreted by stem cells may be able to control the growth of endometriotic lesions. This provides a new therapeutic strategy for the treatment of endometriosis. In animal experiments, intraperitoneal injection of UCMSCs was shown to aggravate endometriosis in macaque models of endometriosis [ 130 ]. Moreover, studies have shown that EMSCs may participate in the formation of endometriotic lesions by changing the body's metabolic pattern and generating immune tolerance [ 131 ]. This information will help us to identify new therapeutic targets for endometriosis. Initially, the therapeutic effects of MSCs were mostly attributable to their homing and differentiation abilities [ 132 ]. However, multiple in vivo studies have suggested that the number of MSCs colonized locally in injured tissue is low in the natural state and that the duration of colonization is usually very short [ 133 ]. Importantly, MSCs cannot be efficiently transformed into parenchymal cell components of organs under noninducing conditions. This finding suggests that the main therapeutic effects of MSCs may be mediated mainly by paracrine mechanisms [ 134 , 135 ]. As one of the main paracrine mechanisms of MSCs, exosomes play a very important role in the therapeutic effects of MSCs [ [136] , [137] , [138] ]. In the future, we should focus on the use of formulation technology to combine therapeutic factors with MSCs, such as the combination of a microparticle system loaded with therapeutic factors and a biological scaffold loaded with stem cells, to achieve better therapeutic effects [ 139 ].

Data sharing is not applicable to this article as no new data were created or analyzed in this study.