# Fibr Facilitates Mesenchymal Stem Cells to Ameliorate Rats with Polycystic Ovary Syndrome
## 3 Discussion  
The primary finding of this study is that UC-MSCs within fibrin hydrogel have shown therapeutic potential by restoring ovarian function and structure in PCOS rats. Our results reveal that direct injection of UC-MSCs alone as well as with fibrin scaffolds elevate serum estradiol and progesterone levels, whereas they significantly decrease gonadotropin (LH/FSH), testosterone, and TGF-\(\beta\)1 levels. Furthermore, estrous cyclicity was restored, and the number of granulosa cells increased, while the number of immature cystic follicles in ovaries decreased in a PCOS rat model. The ovary size and weight significantly increased after intraovarian injection of UC-MSCs alone as well as UC-MSCs with fibrin. Thus, we infer that UC-MSCs can restore the function of damaged ovaries in PCOS rats. However, relatively few studies have examined the use of UC-MSCs combined with fibrin therapy to treat PCOS. The survival time of administered UC-MSCs with the absence of fibrin scaffold in the host ovary was less than one week. No cells migrated to other tissues or organs, demonstrating that it is a risk-free therapeutic approach for PCOS; as previously reported, MSCs in fibrin hardly migrated independent of inflammatory factor and did not increase further on day 5 [32,33]. Depending on the severity of the disease, the accurate dose and optimal administration time must also be established. It is necessary to thoroughly understand the underlying mechanisms that regulate and modulate MSCs. What's more, appropriate methods should be developed. MSCs injection into the ovary under ultrasound guidance is safe and can serve as an effective approach for female patients without damaging or drifting to other tissues [34, 35, 36]. It is feasible for fibrin to supply three-dimensional supports and provide integrin-binding sites for MSCs [31], thus improving MSC adhesion and expansion [37], and allowing MSCs to secrete more bioactive factors to inhibit inflammation, reduce the apoptosis of granule cells, and promote angiogenesis [38]. Besides, fibrin is a common biomaterial in the fields of regenerative medicine and tissue engineering because of its ease of handling and quick preparation [33, 39, 40, 41]. We illustrated that UC-MSCs enwrapped in fibrin can spread more extensively and exhibit higher proliferation rates than those on the surface of fibrin gels. The regenerative use of MSCs to recover ovarian function may thus potentially be applied for the treatment of PCOS. This is the first time that UC-MSCs with fibrin have been used to repair PCOS ovary through intraovarian injection, and the results demonstrated that fibrin facilitated UC-MSCs in repairing PCOS ovaries. Women with PCOS have characteristic neuroendocrine abnormalities, including persistently elevated GnRH pulse frequency [42] and increased production of gonadotropins [43], which lead to abnormal cyclicity [44, 45] and reduced progesterone levels [45]. Estrogen plays a permissive role in progesterone suppression of GnRH pulse frequency [46]. Hyperandrogenemia is another positive feedback to gonadotropin production, and UC-MSCs reduce androgen levels. It provides promising insight into the hormonal regulation of expression in PCOS patients. However, the mechanism by which MSC transplantation promotes normal reproductive hormonal concentrations and hence ovarian function requires further investigation. The application of UC-MSCs in rat models of ovarian dysfunction has been previously reported with positive effects on damaged ovary tissues such as increased E2 levels and anti-inflammatory effects [47]. Additionally, MSCs helped restore ovarian function by downregulating proinflammatory cytokines [47]. PCOS rats showed improved ovarian fibrosis with a TGF-\(\beta\)1 receptor inhibitor [48]. After MSCs navigated to damaged sites, they interacted closely with local stimuli such as cytokines [49].