注射 bone marrow–derived mesenchymal stem cells(BMSC)骨髓間質幹細胞入卵巢可能可以提高退化性卵巢局部功能  為恢復卵巢功能和緩解更年期症狀提供了機會。

從卵巢早衰患者的髂骨骨髓中採集BMSC，並在手術中濃縮富集BMSC中的有核細胞，然後透過腹腔鏡將其註射到患者的右側卵巢中。

Intraovarian injection of autologous human mesenchymal stem cells increases estrogen production and reduces menopausal symptoms in women with premature ovarian failure

Intraovarian administration of human bone marrow–derived mesenchymal stem cells was able to restore ovarian hormone production, reactivate folliculogenesis, and reverse infertility in a chemotherapy-induced ovarian failure mouse model. 

Due to the ability of BMSCs in restoring physiological function of many organs, there are 344 registered clinical trials trying to evaluate the potential of BMSC-based CT against a plethora of human diseases worldwide. BMSCs have been shown to be effective in the treatment of many diseases with the advancement of preclinical studies [31]. Furthermore, MSCs have been shown in almost all tissues. They can be easily isolated from the bone marrow, adipose tissue, umbilical cord, fetal liver, muscle, and lung and can be successfully expanded in vitro [32]. It is better to use freshly isolated MSCs in stem cell therapy, because it has been shown that major histocompatibility complex II molecules could be increased during in vitro expansion of the stem cells, which may increase their allogenicity [33]. Recent studies have suggested that the allogenicity of MSCs has no significant adverse impact on their engraftment in wound healing, though [34]. Multiple studies have also demonstrated the ability of stem cell bioactive factors (the secretome) to restore the ovarian function and regeneration [35–37]. Earlier research primarily attributed the effects of the MSC potential therapy to these cells’ capacity for local differentiation into various tissue types. However, recently, research studies have indicated that implanted MSCs have short lifespans, and their therapeutic benefits could be due to their secretome [38]. The secretome is formed of molecules secreted into the extracellular space and consists of soluble proteins, free nucleic acids, lipids, and extracellular vesicles. These vesicles include apoptotic bodies, microparticles, and exosomes. Gu et al. studied the reparative effects of MSCs on vascular tissues. They found that two mechanisms are involved in vascular regeneration: the MSCs’ multipotent differentiation ability to produce endothelial cells, vascular smooth muscle cells, and other cell types, as well as their capacity to secrete various trophic factors. These factors are potent in promoting angiogenesis, inhibiting apoptosis, and modulating immunoreactions [39].

The immunomodulatory effect of MSCs works through immune cells such as natural killer (NK) cells, B and T cells, and dendritic cell (DC) differentiation and migration [40]. Additionally, coculture of the MSC secretome promotes the anti-inflammatory phenotype of DCs, T cells, macrophages, and NK cells [41, 42]. In addition, the MSC secretome includes a number of molecules, such as prostaglandin E₂, tumor necrosis factor-α-stimulated gene-6, transforming growth factor-β, hepatocyte growth factor (HGF), and interleukin-10, which may mediate the immunomodulatory function of MSCs [43, 44]. 

In the context of POF, the regenerative mechanism of BMSCs in the ovary could be mainly via the promotion of the angiogenesis. 

Like in other reported models, MSCs produce a large variety of humoral factors that may play a role in tubular formation by recruiting ovarian endothelial microvessel cells [45, 46]. The data from our experiments in our lab suggest that the MSC secretome can produce similar effects on human granulosa cells in vitro [47]. In a recent publication by our group, Park et al. reported that the expression of proliferation marker Ki67 was significantly increased by treatment with the MSC secretome in human ovarian endothelial cells [48]. 

MSC secretome treatment also induced significantly higher expression of several angiogenic markers, such as vascular endothelial growth factor (VEGF) receptor 2, Tie2/Tek, VE-cadherin, endoglin, and VEGF, than of matched controls. 

It suggests that the MSC secretome likely contains bioactive factors that can enhance ovarian angiogenesis. 

Other studies have indicated that BMSCs are able to differentiate into endothelial cells, pericytes, or even vessel walls to support the formation of blood vessels [49]. Furthermore, it was suggested that MSCs are also capable of protecting endothelial cells from apoptosis, including oxidative stress–related apoptosis in the initial phase of angiogenesis [50]. 

The role of MSCs in promoting angiogenesis was reported in various studies demonstrating that MSCs support the late phases of angiogenesis, including blood vessel maturation [51, 52]. 

This is also consistent with our preclinical work where estrogen-responsive organs demonstrated remarkable increases in the mean weight, such as for the ovaries, uterus, kidneys, and liver [13]. 

Also, multiple studies demonstrate that transplanted MSCs may play an important role in the ovarian microenvironment paracrine regulation, producing a wide array of cytokines, such as VEGF, insulin-like growth factor-1, and HGF, that inhibit apoptosis [53].