血红素加氧酶1在iPSCs修复宫腔粘连所致子宫内膜损伤中的作用及机制研究

Intrauterine adhesion (IUA) is a common cause for secondary infertility, whose incidence is being increased quickly. However, traditional treatment nowadays can only restore the shape of the uterine cavity but not the inadequate endometrium, not to mention the fertility outcome. Therefore, new treatment options are warranted. In previous studies, we found that transplantation iPSCs in situ could significantly improve the function of impaired endometrium and increase pregnancy rate in an IUA mouse model. However, when knocking down heme-oxygenase-1(HO-1) expression, iPSCs could no longer localize into the impaired endometrium and the therapeutic effect of iPSCs was significantly weakened. However, the mechanism of iPSCs in functionally repairing impaired endometrium of IUA was not yet obvious. In the present study, we try to study the role of HO-1 in endometrium repairing by iPSCs transplantation by means of up/down-regulation HO-1 expression in iPSCs. Furthermore, compare the effect of up/down-regulation HO-1 expression on iPSCs’ cell function, cell differentiation and regulation of TGF-β/Wnt signaling pathways under inflammatory culture environment and control one. The aim of this study is to illuminate the molecular mechanism of HO-1 mediated iPSCs in repairing and reconstructing impaired endometrium in IUA, which would shed light on new intervention targets and provide abundant evidence on cell replacement therapy in treating IUA.

宫腔粘连(IUA)的发病率日趋升高，是导致继发不孕的最常见原因之一。传统的宫腔镜手术临床实际疗效欠佳，因此亟需寻求新的IUA治疗方法。申请人前期发现：宫腔原位移植诱导性多能干细胞(iPSCs)，可促进IUA模型小鼠子宫内膜损伤后的再生和功能恢复，并改善小鼠远期妊娠率。但当血红素加氧酶1(HO-1)表达受到干扰后，可显著影响iPSCs的定位及其修复作用，进而小鼠远期妊娠率显著降低。但这一调控作用的分子机制尚未阐明，因此本项目拟通过：1）建立IUA小鼠模型，明确HO-1在iPSCs促进子宫内膜损伤修复中的作用；2）体外模拟IUA发生的炎性环境，阐明HO-1是否发挥其抗炎抗氧化作用，调控iPSCs细胞的功能及分化成熟，并探讨TGF-β和Wnt信号通路对IUA子宫内膜纤维化进程的交叉对话是否受到HO-1的调控，以期为iPSCs自体细胞替代治疗IUA的临床应用提供更系统深入的科学依据及新的干预靶点。

本课题我们立足于探索宫腔粘连进行细胞治疗的分子机制。我们发现以多能干细胞作为种子细胞，可促进IUA模型小鼠子宫内膜损伤后的再生和功能恢复，并提高小鼠远期的妊娠率。在此过程中，抗氧化关键调控因子血红素加氧酶1(HO-1)的表达水平可显著影响iPSCs的定位及其修复作用。HO-1可同时激活TGF-β、P53等通路，引起细胞抗炎因子的分泌以及细胞增殖及粘附相关基因表达的改变，进而影响iPSCs对受损内膜的修复。我们将进一步探索HO-1激活剂能否既改善宫内炎性微环境，又更有效促进iPSCs自体细胞替代治疗IUA的疗效，从而为临床治疗提供新的思路。