ΔNp63调控宫腔粘连子宫内膜纤维化的机制研究

Intrauterine adhesions (IUA) are a disease characterized by endometrial fibrosis after injury of endometrial basal layer. IUA is an important cause of uterine associated infertility and there is no effective treatment for it. Our previous study found that ΔNp63, an important molecular for regulation of epithelial mesenchymal transition (EMT) was significantly increased in residual endometrial epithelial cells from patients with IUA and promoted the endometrial fibrosis. In vitro experiments showed that ΔNp63-expressed human endometrial epithelial cells showed inhibition of proliferation and differentiation and a tendency of differentiation into myofibroblast. Additionally, using fibrosis inducing drug to treat primary endometrial epithelial cells, the cells showed high expression of ΔNp63 along with phenotype switch from epithelium to myofibroblast. On the contrary, basic fibroblast growth factor (bFGF) recovered the proliferation of epithelial cells, reversed the EMT process and suppressed the fibrosis by inhibiting the expression of ΔNp63. Our scientific hypotheses are: (1) endometrial damage induces the residual endometrial epithelial reprogramming, promoting the expression of ΔNp63; (2) high expression of ΔNp63 blocks the proliferation and differentiation of endometrial epithelium into endometrial epithelial cells, but into myofibroblast; (3) bFGF could reverse the abnormal signal transduction in which ΔNp63 as the central molecular in IUA, promoting the functional endometrial regeneration.

宫腔粘连（IUA）是子宫内膜基底层损伤后以内膜纤维化为特征的疾病，是子宫性不孕的重要原因。目前缺乏有效治疗方法。我们前期研究发现调控上皮-间质转化（EMT）的重要分子ΔNp63在IUA残存内膜上皮细胞显著高表达，并促进内膜纤维化。体外实验证明，高表达ΔNp63的子宫内膜上皮细胞增殖及分化被抑制，并有向肌成纤维细胞分化倾向。用诱导纤维化药物刺激子宫内膜上皮细胞，诱导出ΔNp63高表达，且上皮表型向成纤维细胞转化。相反，碱性成纤维细胞生长因子（bFGF）可通过抑制ΔNp63表达，恢复上皮自身增殖能力，逆转EMT过程，遏制纤维化。我们的科学假说是：①子宫内膜损伤诱导残存内膜上皮重编程，使其高表达ΔNp63；②异源性高表达ΔNp63的子宫内膜上皮不能增殖并分化成内膜上皮细胞，而是向肌成纤维细胞转分化；③bFGF可逆转宫腔粘连时以ΔNp63为中心的异常分子信号转导机制，从而促进功能性子宫内膜再生。

宫腔粘连（IUA）是子宫内膜严重损伤后以内膜纤维化为特征的疾病，是子宫性不孕的重要原因。目前缺乏有效治疗方法。本研究揭示并证实：1.重度IUA患者子宫内膜上皮细胞（EEC）高表达ΔNp63α，ΔNp63α抑制EEC增殖，诱导EEC向肌成纤维细胞转分化（EMT），促进内膜纤维化；2. 转录组分析发现ΔNp63α高表达后激活EMT相关通路；3. 明确ΔNp63α促进EMT的关键转录因子SNAI1在EEC中高表达；4. 证实ΔNp63α下调EECs中GSK3β的表达；5. 证实ΔNp63α通过DUSP4下调GSK3β的表达；6. 证实bFGF可在体外逆转ΔNp63α诱导的EEC-EMT；7.证实 bFGF促进IUA小鼠模型子宫内膜功能性再生；8. 进行了重组人bFGF治疗瘢痕化薄型内膜所致不孕症的临床转化研究；9. 发现在子宫内膜纤维化及EEC-EMT过程中发挥重要作用的其他分子。以上结果表明，EEC-EMT是IUA患者的重要病理改变；ΔNp63α是调控EEC-EMT的关键基因，其可通过DUSP4/GSK3B/SNAI1信号通路诱导EEC-EMT，从而引起子宫内膜纤维化。bFGF可通过抑制上述信号通路，逆转ΔNp63α诱导的EEC-EMT，从而缓解子宫内膜纤维化。临床初步试验进一步证明bFGF可促进子宫内膜功能性再生。