LncRNA MALAT1调控母胎界面MSCs参与子痫前期发病的机制研究

Pre-eclampsia is a severe pregnancy-specific disorder. Defective angiopoiesis of maternal-fetal interface is one of the most favored pathogenesis. As is well known, mesenchymal stem cells (MSCs) have the function of regulating angiogenesis. In our previous studies, we found that MSCs from maternal-fetal interface of patients with PE presented slow growth and abnormal function which associated with miR-16 targeting CCNE1 and VEGFA expression. We also found that long non-coding RNA (LncRNA) MALAT1 was significantly deceresed in decidua derived MSCs from patients with PE. The functions of microRNA can be regulated by the LncRNA. We predicted that LncRNA MALAT1 can combine miR-16 using bioinformatics methods. We suppose that decreased MALAT1in decidua MSCs lost the effective regulation of miR-16, and then inhibit the expression of CCNE1 and VEGFA, which result in growth restriction and regulation of angiogenesis dysfunction of MSCs, and finally lead to the occurrence of PE. Our project is to investigate the effects of MALAT1 on MSCs’proliferation and function; to explore the mechanisms of MALAT1 in regulating decidua MSCs to affect angiogenesis via inhibiting miR-16; to assess the effects of MALAT1 on blood pressure, urine protein and other preeclampsia related indicators in miR-16 overexpressed pregnant rats. We will provide new insight and technology to understand pathogenesis of pre-eclampsia and find new effective method to prevent and cure this disease.

子痫前期（PE）是妊娠常见的严重并发症，母胎界面血管形成障碍被认为是其发病机制之一。已知间充质干细胞（MSC）具有调节血管形成功能，我们前期发现PE患者母胎界面MSC生长及功能异常与miR-16靶向CCNE1及VEGFA有关。我们还发现长链非编码RNA（LncRNA）MALAT1在PE患者蜕膜MSC中显著下调。LncRNA 可调控microRNA，生物信息学方法预测MALAT1能够结合miR-16。故推测：蜕膜MSC低表达MALAT1失去对miR-16的有效调控，从而抑制CCNE1及VEGFA表达，引起MSC生长受限和调节血管形成障碍而诱发PE。本项目将分析MALAT1对蜕膜MSC的影响；揭示MALAT1/miR-16调控蜕膜MSC影响血管形成的机制；体内评估MALAT1调控miR-16对子宫螺旋动脉重铸的作用。本项目的完成将为揭示PE的发病机制和寻求新的有效防治方法提供新思路和新技术。

子痫前期（PE）是严重妊娠并发症。我们前期研究发现母胎界面间充质干细胞（MSCs）在PE发生发展过程中发挥重要作用，但是分子调控机制有待进一步探索。本研究以MSCs为模型，结合临床调查，探讨了长链非编码RNA MALAT1以及miR-495和miR-494对MSCs生长和功能的影响。我们做了以下工作：1、明确了MALAT1、miR-495和miR-494等关键分子在PE患者中的表达情况；2、发现MALAT1不影响MSCs的表面标志和分化能力；3、发现MALAT1可通过调控VEGF表达影响MSCs生长、迁移、侵袭和调节血管形成的能力；4、发现MALAT1通过促进IDO的产生影响MSCs对巨噬细胞极化的调控；5、发现氧化应激是导致MSCs低表达MALAT1的原因；6、初步构建了MALAT1低表达动物模型，有待进一步评测PE表型；7、发现miR-495通过靶向Bmi-1诱导MSCs衰老，从而导致细胞生长、迁移、侵袭及调节血管形成能力的降低；8、研究了miR-494影响MSCs生长和功能的分子调控机制。以上结果表明，MALAT1及miR-495/494在PE患者脐带及脐带来源的MSCs中表达异常，导致MSCs生长、血管调节和免疫抑制功能障碍，而这种调控异常是PE发病的重要机制之一。