改良型IUD辅助经血干细胞重建在位子宫内膜的研究

Endometrial repair mainly relys on stem cells in the basal. Treatments of intrauterine adhesions, representative of endometrial injury, can not compensate the lack of stem cells. Endometrial stem cells and uterine cavity provide the clinical possibility and feasibility of topical stem cell therapy, not also avoiding the worry of endometriosis with Systemic administration and loss of stem cells because of stem cell homing, but also providing niche of stem cell differentiation. Applicants designed a modified IUD (intrauterine device), traditional IUD as frame (containing drug delivery system) and biofilms in the middle of the IUD (as physical barrier and stem cell carrier). Mechanism of stem cell differentiation is still unknown. Studies have shown that estrogen (E) is an important factor for stem cell differentiation. E can activate several kinases including PKA through non-genomic pathway with the deficiency of ER. It has been testified that cAMP / PKA / CREB pathway play an important role in stem cell differentiation. Then it is speculated that E might mediate differentiation from stem cell to endometrium via cAMP / PKA / CREB pathway. This study aims to treat uterine adhesions with modified IUD combined with self stem cells, observe endometrial stem cell differentiation, and investigate the mechanism of endometrial stem cell differentiation in vitro.

子宫内膜的修复主要依靠基底层干细胞。以宫腔粘连为代表的内膜损伤治疗方案并不能弥补干细胞的缺失。经血干细胞的发现和子宫腔的独特形态为干细胞局部治疗提供了临床可行性，避免了干细胞全身输注引发子宫内膜异位症的担忧及干细胞归巢导致的细胞游走和丢失，还提供了干细胞分化时所需的微环境。申请者由此设计了改良型IUD，以传统IUD作为支架（内置药物缓释系统），在环的中央放置生物膜（作为物理屏障和干细胞载体）。干细胞向子宫内膜分化的机制尚不清楚，研究显示雌激素（E）是一个重要的诱导因子。E可通过膜受体（mER）非基因组途径激活包括PKA在内的多种激酶。已证实cAMP/PKA/CREB通路在干细胞分化过程起着重要调控作用，由此推测E可能介由cAMP/PKA/CREB通路调控干细胞向子宫内膜的分化。本研究拟制作改良型IUD，联合自体经血干细胞治疗宫腔粘连，观察干细胞向子宫内膜的分化，并通过体外实验探讨分化机制。

子宫内膜的修复主要依靠基底层干细胞。以宫腔粘连为代表的内膜损伤治疗方案并不能弥补干细胞的缺失。经血干细胞的发现和子宫腔的独特形态为干细胞局部治疗提供了临床可行性，避免了干细胞全身输注引发子宫内膜异位症的担忧及干细胞归巢导致的细胞游走和丢失，还提供了干细胞分化时所需的微环境。申请者已经成功提取经血干细胞，并且通过干细胞标志物的检测、体内外成瘤试验、体外多向诱导分化试验等证实经血干细胞的特性；同时，在与正常子宫内膜间质细胞共培养中成功诱导经血干细胞为成熟子宫内膜细胞，目前仍在寻找关键诱导因子中。申请者以传统IUD为支架，中间覆盖三层膜状结构，外层为可吸收的干细胞承载系统，中间层为不可吸收的物理屏障部分。IUD材质已选取成功，均已临床运用，目前正在与相关机构商谈制作事宜。宫腔粘连的动物模型已制备成功，由于经血干细胞储备不足，尚未开展动物体内实验，正在积极储备经血干细胞中。如果实验论证成功并且成功运用于临床，将可以利用自身经血干细胞和天然通道治疗宫腔粘连，改善月经不调及女性不孕不育难题，避免伦理争议、交叉感染，从根本上解决子宫内膜问题。