Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea.
Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine Hospital, Bucheon, Gyunggi-do, 14584, Republic of Korea.
Lab Invest. 2021 Mar;101(3):304-317. doi: 10.1038/s41374-020-00513-1. Epub 2020 Dec 10.
Angiogenesis plays an important role in damaged organ or tissue and cell regeneration and ovarian development and function. Primary ovarian insufficiency (POI) is a prevalent pathology in women under 40. Conventional treatment for POI involves hormone therapy. However, due to its side effects, an alternative approach is desirable. Human mesenchymal stem cells (MSCs) from various sources restore ovarian function; however, they have many limitations as stem cell sources. Therefore, it is desirable to study the efficacy of placenta-derived MSCs (PD-MSCs), which possess many advantages over other MSCs, in a rat model of ovarian dysfunction. Here, we investigated the restorative effect of PD-MSCs on injured ovaries in ovariectomized (OVX) rats and the ability of intravenous transplantation (Tx) of PD-MSCs (5 × 10) to enhance ovarian vasculature and follicular development. ELISA analysis of serum revealed that compared to the non-transplantation (NTx) group, the Tx group showed significantly increased levels of anti-Müllerian hormone, follicle stimulating hormone, and estradiol (E2) (*P < 0.05). In addition, histological analysis showed more mature follicles and less atresia and restoration of expanded blood vessels in the ovaries of the OVX PD-MSC Tx group than those of the NTx group (*P < 0.05). Furthermore, folliculogenesis-related gene expression was also significantly increased in the PD-MSC Tx group (*P < 0.05). Vascular endothelial growth factor (VEGF) and VEGF receptor 2 expressions were increased in the ovaries of the OVX PD-MSC Tx group compared to the NTx group through PI3K/AKT/mTOR and GSK3β/β-catenin pathway activation. Interestingly, ex vivo cocultivation of damaged ovaries and PD-MSCs or treatment with recombinant VEGF (50 ng/ml) increased folliculogenic factors and VEGF signaling pathways. Notably, compared to recombinant VEGF, PD-MSCs significantly increased folliculogenesis and angiogenesis (*P < 0.05). These findings suggest that VEGF secreted by PD-MSCs promotes follicular development and ovarian function after OVX through vascular remodeling. Therefore, these results provide fundamental data for understanding the therapeutic effects and mechanism of stem cell therapy based on PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.
血管生成在受损器官或组织和细胞再生以及卵巢发育和功能中起着重要作用。原发性卵巢功能不全（POI）是 40 岁以下女性中常见的病理学。POI 的常规治疗涉及激素治疗。然而，由于其副作用，需要一种替代方法。来自各种来源的人骨髓间充质干细胞（MSCs）可恢复卵巢功能；然而，作为干细胞来源，它们有许多限制。因此，研究胎盘来源的间充质干细胞（PD-MSCs）在卵巢功能障碍大鼠模型中的疗效是可取的，它比其他 MSCs 具有许多优势。在这里，我们研究了 PD-MSCs 对去卵巢（OVX）大鼠受损卵巢的修复作用，以及静脉移植（Tx）PD-MSCs（5×10）增强卵巢血管生成和卵泡发育的能力。血清 ELISA 分析显示，与非移植（NTx）组相比，Tx 组抗苗勒管激素、卵泡刺激素和雌二醇（E2）水平显著升高（*P<0.05）。此外，组织学分析显示，OVX PD-MSC Tx 组的卵巢中成熟卵泡更多，闭锁较少，扩张的血管得到恢复，而 NTx 组则较少（*P<0.05）。此外，PD-MSC Tx 组的卵泡发生相关基因表达也显著增加（*P<0.05）。OVX PD-MSC Tx 组的卵巢中血管内皮生长因子（VEGF）和 VEGF 受体 2 的表达通过 PI3K/AKT/mTOR 和 GSK3β/β-catenin 途径的激活而增加。有趣的是，与 NTx 组相比，受损卵巢与 PD-MSC 体外共培养或用重组 VEGF（50ng/ml）处理均增加了卵泡生成因子和 VEGF 信号通路。值得注意的是，与重组 VEGF 相比，PD-MSCs 显著增加了卵泡发生和血管生成（*P<0.05）。这些发现表明，PD-MSCs 分泌的 VEGF 通过血管重塑促进 OVX 后卵泡发育和卵巢功能。因此，这些结果为理解基于 PD-MSCs 的干细胞治疗的治疗效果和机制提供了基础数据，并为其在包括不孕和更年期在内的妇产科疾病中的应用提供了理论基础。
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