转化生长因子复合脂肪源性干细胞调控改造盆腔器官脱垂病理微环境的机制和效应研究

The incidence of pelvic organ prolapse (POP) is close to 25% among women over 60-year-old in China. The sever syndromes result in a major health and quality-of-life problem affecting adult and elder women. Limitation in current treatments existed. Research showed that the elastin of the pelvic connective tissue was damaged or even lack in the POP patients. And Lysyl Oxidase-Like-1 (LOXL1), which plays an important role in the polymerization process of elastic fiber in pelvic support organizations, was decreased significantly. However, research and treatment for this clearly pathological mechanism is not clear. Based on treating stress urinary incontinence successfully with stem cells (Zou XH, Biomaterials 2010), we make a hypothesis that implantation of adipose-derived stem cells (ADSCs) induced by transforming growth factor (TGF-β) can reverse the pathological micro-environment in the POP by regulating the expression of LOXL1 . This subject will further explain the pathogenesis of POP fro2m histological, cellular and molecular level. And it also will make clear on how TGF-β regulate LOXL1 and promote the synthesis of ECM. So we can evaluate the effect of intervening POP through tissue engineering method which based on TGF-β , ADSCs and scaffold. Our finding will provide practical basis and new ideas for clearing the pathological mechanism of POP.

我国60岁以上妇女盆腔器官脱垂（POP）的发病率接近25%，其症状严重影响妇女健康和生活质量，现有治疗手段存在一定局限性。研究表明，POP患者盆腔结缔组织的弹性蛋白受损甚至缺失，而调控弹性蛋白合成的类赖氨酰氧化酶1（LOXL1）分泌明显降低，但目前针对这一较明确病理机制的治疗手段和研究尚属空白。本研究组在前期用干细胞成功治疗压力性尿失禁（Zou XH, Biomaterials 2010）的基础上提出假说：TGF-β结合脂肪源性干细胞（ADSCs）可通过调控LOXL1的表达和弹性蛋白合成来逆转POP盆底组织病理微环境和进程。本课题将从组织、细胞和分子层面进一步明确POP的病理机制，探明TGF-β调控LOXL1的表达和增加弹性蛋白分泌的效应和机制，评估以TGF-β和ADSCs为基础的组织工程手段干预POP的效应。研究发现将为明确POP的机制及探寻针对病理机制的治疗手段提供实用基础和新思路。

盆腔器官脱垂（POP）是困扰中老年妇女的常见病，目前尚缺乏能够针对病因的治疗方法。前期结果显示POP病人的阴道组织中弹性纤维排列紊乱、含量减少，证实了盆底支持结构破坏可能成为POP的病理因素。我们发现LOXL1（该基因对弹性蛋白的合成和交联起重要作用）敲除老鼠不仅会出现POP表型，且盆底弹性纤维及胶原合成和排列也出现紊乱，因此本研究采用LOXL1基因敲除老鼠作为动物模型。制作了一种脂肪来源干细胞（ADSCs）复合丝素微球(ZOU XH，Biomaterials 2014)，再用TGFb1处理，结果显示种植在丝素微球中的ADSCs用TGFb1处理后，lox家族成员以及弹性蛋白的基因表达量上调。我们将复合ADSC的丝素微球对模型小鼠进行盆底注射，期望增加局部细胞外基质的合成和交联，逆转模型小鼠脱垂表型。本研究期望通过调控干细胞的表达来调控弹性蛋白的合成，并复合组织工程技术手段，为POP的临床治疗提供新思路。本项目成果达到结题预期，发表高影响因子SCI论文1篇，在投1篇，申请国家发明专利1项，获得省部级二等奖1项，培养博士后1名博士1名硕士2名。