人脐带间充质干细胞移植对子宫内膜容受性的影响与 Th1/Th2 平衡改变及 uNK 细胞在自身免疫性卵巢早衰小鼠子宫中的表达有关。

The effects of human umbilical cord-derived mesenchymal stem cell transplantation on endometrial receptivity are associated with Th1/Th2 balance change and uNK cell expression of uterine in autoimmune premature ovarian failure mice.

机构信息

College of Basic Medicine, Binzhou Medical University, Yantai, 264003, Shandong, China.

College of Basic Medicine & Institute of Reproductive Diseases, Binzhou Medical University, Yantai, 264003, Shandong, China.

出版信息

Stem Cell Res Ther. 2019 Jul 22;10(1):214. doi: 10.1186/s13287-019-1313-y.

BACKGROUND

To explore the mechanism of human umbilical cord-derived mesenchymal stem cell (hUMSC) transplantation to improve ovarian function and the endometrial receptivity in autoimmune premature ovarian failure (POF) mice.

METHODS

The POF model was established in mice treated with zona pellucida 3 polypeptide fragment (zona pellucida 3, ZP3). The hUMSCs were transplanted into the POF mice through tail vein injection. Following the transplantation, the serum hormone levels of follicle stimulating hormone (FSH), estrogen (E), progesterone (P), γ-interferon (IFN-γ), interleukin-2 (IL-2), and interleukin-4 (IL-4) were evaluated by ELISA analysis. Morphological changes of ovarian and uterus tissues were examined by HE staining and immunohistochemistry. The expression of Th1/Th2 cytokines of T cells in spleen and CD56CD16 cells (uterine natural killer cells, uNK cells) in uterine was measured by flow cytometry (FCM) and immunohistochemistry. The expression of HOXA10 in uterine endometrium was examined by immunohistochemistry and RT-PCR analysis. The pinopodes of epithelial cells in uterine endometrium were examined by scanning electron microscopy.

RESULTS

Following hUMSC transplantation, the serum levels of E, P, and IL-4 were increased but FSH, IFN-γ, and IL-2 levels were decreased in POF mice. Also, the transplantation of hUMSCs caused an increase in total number of healthy follicles and decrease of atresia follicles. The expression of HOXA10 gene was significantly increased but the CD56CD16 uNK cells decreased in the endometrium of uterine. The ratio of Th1/Th2 cytokines was also significantly decreased.

CONCLUSION

The data suggest that the recovery of ovarian function and endometrial receptivity in POF mice was regulated by the balance of Th1/Th2 cytokines and expression of uNK cells in the endometrium following hUMSC transplantation.

背景

探索人脐带间充质干细胞（hUMSC）移植改善自身免疫性卵巢早衰（POF）小鼠卵巢功能和子宫内膜容受性的机制。

方法

用透明带 3 多肽片段（ZP3）处理建立 POF 小鼠模型，通过尾静脉注射将 hUMSC 移植到 POF 小鼠中。移植后，通过 ELISA 分析评估血清卵泡刺激素（FSH）、雌激素（E）、孕激素（P）、γ-干扰素（IFN-γ）、白细胞介素-2（IL-2）和白细胞介素-4（IL-4）水平。通过 HE 染色和免疫组织化学检查卵巢和子宫组织的形态变化。通过流式细胞术（FCM）和免疫组织化学检查脾 T 细胞 Th1/Th2 细胞因子和子宫内 CD56CD16 细胞（子宫自然杀伤细胞，uNK 细胞）的表达。通过免疫组织化学和 RT-PCR 分析检查子宫子宫内膜 HOXA10 的表达。通过扫描电子显微镜检查子宫内膜上皮细胞的顶端突起。

结果

hUMSC 移植后，POF 小鼠血清 E、P 和 IL-4 水平升高，FSH、IFN-γ和 IL-2 水平降低。此外，hUMSC 移植导致总健康卵泡数量增加，闭锁卵泡数量减少。子宫内膜 HOXA10 基因表达明显增加，但子宫内膜内 CD56CD16 uNK 细胞减少。Th1/Th2 细胞因子的比例也明显降低。