Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China.
Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.
J Ovarian Res. 2023 Mar 21;16(1):58. doi: 10.1186/s13048-023-01136-y.
Premature ovarian insufficiency (POI) is a common clinical problem, however, there are currently no effective therapies. Pyroptosis induced by the NLRP3 inflammasome is considered a possible mechanism of POI. Placental mesenchymal stem cells (PMSCs) have excellent immunomodulatory potential and offer a promising method for treating POI.
Female Sprague-Dawley rats were randomly divided into four treatment groups: control (no POI), POI with no PMSCs, POI with PMSCs transplant, and POI with hormones (estrogen + progesterone) as positive control. POI was induced by exposure to 4-vinylcyclohexene diepoxide (VCD) for 15 days. After four weeks, all animals were euthanized and examined for pathology. Hormone levels were measured and ovarian function was evaluated in relation to the estrous cycle. Levels of NLRP3 inflammasome pathway proteins were determined by immunohistochemistry and western blot.
VCD significantly damaged rat follicles at different estrous stages. Injection of human PMSCs improved ovarian function and reproductive ability of POI rats compared to the sham and hormone groups. Our data also showed that PMSCs markedly suppress cell pyroptosis via downregulation of the NLRP3 inflammasome, caspase-1, IL-1β and IL-18 compared to the other two groups. The human PMSCs increased the expression of IL-4 and IL-10 and decreased pro-inflammatory factors by phenotypic changes in macrophages.
Our findings revealed a novel mechanism of follicular dysfunction and ovarian fibrosis via activation of the NLRP3 inflammasome followed by secretion of pro-inflammatory factors. Transplantation of PMSCs into POI rats suppressed pro-inflammatory factor production, NLRP3 inflammasome formation and pyroptosis, and improved ovarian function.
卵巢早衰（POI）是一种常见的临床问题，但目前尚无有效的治疗方法。NLRP3 炎性体诱导的细胞焦亡被认为是 POI 的一种可能机制。胎盘间充质干细胞（PMSCs）具有出色的免疫调节潜力，为治疗 POI 提供了一种有前途的方法。
将雌性 Sprague-Dawley 大鼠随机分为四组治疗：对照组（无 POI）、无 PMSCs 的 POI 组、PMSCs 移植的 POI 组和激素（雌激素+孕酮）阳性对照组的 POI 组。用 4-乙烯环己烯二氧化物（VCD）处理 15 天诱导 POI。四周后，所有动物均安乐死并进行病理检查。测定激素水平，评估发情周期与卵巢功能的关系。通过免疫组织化学和 Western blot 测定 NLRP3 炎性体通路蛋白的水平。
VCD 对不同发情期大鼠卵泡有明显损伤。与假手术和激素组相比，人 PMSCs 注射可改善 POI 大鼠的卵巢功能和生殖能力。我们的数据还表明，与另外两组相比，PMSCs 通过下调 NLRP3 炎性体、半胱天冬酶-1、IL-1β 和 IL-18，显著抑制细胞焦亡。人 PMSCs 通过巨噬细胞表型改变增加 IL-4 和 IL-10 的表达并降低促炎因子。
我们的研究结果揭示了一种新的机制，即通过 NLRP3 炎性体的激活和促炎因子的分泌导致卵泡功能障碍和卵巢纤维化。将 PMSCs 移植到 POI 大鼠中可抑制促炎因子的产生、NLRP3 炎性体的形成和细胞焦亡，从而改善卵巢功能。
