Immunomodulatory effect of human amniotic epithelial cells on restoration of ovarian function in mice with autoimmune ovarian disease
Immunomodulatory effect of human amniotic epithelial cells on restoration of ovarian function in mice with autoimmune ovarian disease
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人羊膜上皮细胞对自身免疫性卵巢疾病小鼠卵巢功能恢复的免疫调节作用
DOI：
10.1093/abbs/gmz065
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发表时间：
2019
影响因子：
3.7
通讯作者：
Lai Dongmei
中科院分区：
文献类型：
--
作者：
Zhang Qiuwan;Huang Yating;Sun Junyan;Gu Tingting;Shao Xiaoyan;Lai Dongmei
自身免疫性卵巢疾病（AOD）被认为是卵巢早衰（POF）的主要原因。人羊膜上皮细胞（hAECs）的免疫调节特性已经在许多疾病模型中进行了研究。我们以前报道过hAECs可以恢复化疗诱导的卵巢早衰小鼠的卵巢功能，但hAECs的免疫调节机制尚不清楚。为了研究hAECs对受体小鼠，特别是调节性Treg细胞的影响，将hAECs和hAEC-CM静脉注射到用透明质酸蛋白3肽（pZP 3）免疫的AOD小鼠。通过动情周期、激素分泌、卵泡发育和细胞凋亡分析评价卵巢功能。流式细胞仪检测脾脏中的免疫细胞（CD 3、CD 4、CD 8和Treg细胞）。为探讨hAEC-CM对巨噬细胞功能的影响，建立了脂多糖（LPS）诱导的RAW264.7细胞体外炎症模型。hAECs和hAEC-CM可调节AOD小鼠的动情周期，促进卵泡发育，减轻卵巢细胞凋亡和纤维化。hAEC-CM通过上调巨噬细胞M2基因的表达，显著抑制LPS诱导的RAW 264. 7细胞炎症反应。进一步的研究表明，hAEC分泌的转化生长因子β和巨噬细胞抑制因子在炎症刺激下的巨噬细胞极化和迁移中发挥重要作用。总之，hAECs通过上调脾脏中的Treg细胞来恢复卵巢功能，并通过以旁分泌方式调节AOD小鼠卵巢中活化的巨噬细胞功能来减少炎症反应。
Autoimmune ovarian disease (AOD) is considered to be a major cause of premature ovarian failure (POF). The immunomodulatory properties of human amniotic epithelial cells (hAECs) have been studied in many disease models. We previously reported that hAECs restored ovarian function in chemotherapy-induced POF mice, but the immunomodulatory mechanism of hAECs is still unclear. To investigate the effect of hAECs on recipient mice, especially on regulatory Treg cells, hAECs and hAEC-conditioned medium (hAEC-CM) were intravenously injected into AOD mice immunized with zona pellucida protein 3 peptides (pZP3). Ovarian function was evaluated through estrous cycle, hormone secretion, follicle development, and cell apoptosis analysis. Immune cells including CD3, CD4, CD8 and Treg cells in the spleens were tested by flow cytometry. To elucidate the effect of hAEC-CM on macrophage function, inflammation modelin vitrowas established in RAW264.7 cells induced by lipopolysaccharide (LPS). hAECs and hAEC-CM regulated estrous cycles, promoted follicle development, ameliorated cell apoptosis and fibrosis in ovaries of AOD mice. In addition, hAECs significantly reversed the decrease of pZP3-induced Treg cells in the spleens.In vitro, hAEC-CM significantly inhibited the inflammatory reaction induced by LPS in RAW264.7 cells via up-regulating the expression of M2 macrophage genes. Further study demonstrated that hAEC-secreted transforming growth factor-beta and macrophage inhibitory factor played important roles in the macrophage polarization and migration under inflammatory stimulation. Taken together, hAECs restored ovarian function by up-regulating Treg cells in the spleens and reduced the inflammatory reaction via modulating the activated macrophage function in a paracrine manner in the ovaries of AOD mice.