雌激素诱导骨髓间充质干细胞分化在内异症发生中的作用机制研究

The etiology of Endometriosis (EMs) is unclear and a new hypothesis has been raised and recognized recently-- EMs stem cell origin theory. It speculates the origin and development of ectopic lesions could be differentiated from stem cells, and the bone marrow stem cell might be an important source. In our previous study, we had confirmed that the mice bone marrow mesenchymal stem cells could differentiate into endometrial epithelium cells (EEC) both in vivo and in vitro study and estrogen might play a role key in their differentiation. As EMs is an estrogen dependent disease, we propose the hypothesis -- whether estrogen regulates endometrial stromal cells (ESC) through secreting chemokines to recruit mesenchymal stem cells to endometriotic lesion, and acts on the stem cells directly or induce the stem cells differentiation into EECs through adjusting the ESCs function indirectly; in turn, whether the differentiated EECs could regulate ESCs biological behavior including growth and invasion and then affect the occurrence and development of EMs. This study focuses on the molecular mechanism of estrogen function on bone marrow mesenchymal stem cell recruitment and differentiation, but also the regulation mechanism of the differentiated EECs on the biological behavior of ESCs. The project is expected to improve the EMs stem cell origin theory and provide a scientific evidence for the clinical drug target treatment.

子宫内膜异位症（EMs）病因机制不明，近年来一种新的病因假说逐渐发展并被认可——EMs的干细胞起源学说，其推测异位病灶可能是由干细胞分化而来，骨髓干细胞可能是其重要来源之一。本课题组前期体内外实验均证实小鼠骨髓间充质干细胞可向子宫内膜腺上皮（EEC）方向分化，且雌激素促进该分化过程。鉴于EMs为雌激素依赖性疾病，我们提出假设：探讨雌激素是否通过调节子宫内膜间质细胞（ESC）分泌趋化因子来招募骨髓间充质干细胞至内异病灶，进而雌激素直接诱导干细胞或通过调节ESC功能间接诱导干细胞向EEC分化；反过来，分化的EEC是否调节ESC的生长和侵袭等生物学行为，进而影响EMs的发生与发展。因此本课题拟通过体外实验着重研究雌激素对骨髓间充质干细胞招募和分化调节的分子机制及其分化后形成的EEC对ESC的生物学行为的调节机制。该项目有望进一步完善EMs干细胞起源学说，并为EMs的临床药物靶向治疗提供科学依据。

子宫内膜异位症（EMs）病因机制不明，近年来一种新的病因假说逐渐发展并被认可-EMs的干细胞起源学说，其推测异位病灶可能是由干细胞分化而来，骨髓干细胞可能是其重要来源之一。本课题组前期体内外实验均证实小鼠骨髓间充质干细胞可向子宫内膜腺上皮（EEC）方向分化，且雌激素促进该分化过程。鉴于EMs为雌激素依赖性疾病，我们提出假设：探讨雌激素是否通过调节子宫内膜间质细胞（ESC）分泌趋化因子来招募骨髓间充质干细胞至内异病灶，进而雌激素直接诱导干细胞或通过调节ESC功能间接诱导干细胞向EEC分化；反过来，分化的EEC是否调节ESC的生长和侵袭等生物学行为，进而影响EMs的发生与发展。我们的体外研究结果证实ESC可促进BMSC的迁移，添加雌激素后，BMSC的迁移能力更加增强。17β雌二醇可能通过促进ESC分泌趋化因子，其可促进25种趋化因子表达量明显增加，以SDF-1a为主要作用靶点。17β雌二醇促进BMSC趋化迁移，促使BMSC迁移至适宜的微环境，在一定微环境下定向分化为子宫内膜细胞。动物实验进一步证实17β-雌二醇可能通过促进BMSC迁移、分化、增殖，最终促进异位病灶子宫内膜间质细胞的分化、增殖并减少凋亡，从而增加异位病灶的病变程度。因此本课题通过着重研究雌激素对骨髓间充质干细胞招募的分子机制及其分化后形成的EEC对ESC的生物学行为的调节。该项目进一步完善、验证了EMs干细胞起源学说，并为EMs的临床药物靶向治疗提供科学依据。