胎盘血管形成和血液循环建立机制研究

胎盘循环的建立对胎儿的存活及母婴健康至关重要，但目前对胎盘血管谱系来源和调控机制所知甚少。前期研究发现转录因子Isl1在尿囊前体细胞中特异性表达，Isl1谱系细胞能够分化成脐带和胎盘绒毛膜-迷路层血管和间质细胞。敲除Isl1导致脐带和胎盘血管形成障碍。推测尿囊Isl1前体细胞能够分化成多种胎盘血管和脐带血管和间质细胞，其中Isl1起着重要作用。通过遗传和表观遗传机制Isl1调控了尿囊前体细胞的时空分化以及胎盘和脐带血管和间质的形成。利用Isl1敲除和谱系示踪小鼠模型，我们将阐明尿囊前体细胞，胎盘脐带血管和间质细胞特征，分类和时空分化通路以及Isl1的作用；探讨Isl1在胎盘/脐带血管和间质的形成以及在母婴循环建立的各个关键环节中的作用；阐明尿囊及其谱系细胞对绒毛膜滋养层细胞发育的作用机制。本研究将为妊娠相关疾病的诊断提供基础。

Despite its critical clinical importance, the placenta is the least understood human organ. Great progress has been made in our understanding of the roles of trophoblasts in multiple processes of placental development, however, little is known about the role of the mesenchymal and vascular cells of allantois in placental development, partially due to the lack of a tool to specifically label these cells. LIM homeodomain transcription factor Isl1 is a marker of progenitors of the second heart field, and plays a critical role in cardiac development. Our preliminary study revealed that Isl1 marked the progenitors in allantois core domain (ACD) that contributed to nearly all mesenchymal and vascular endothelial and smooth muscle cells of the placenta and umbilical cord. Similar to that observed in the heart, Isl1 expression is turned off when allantoic Isl1+ progenitors migrate out of ACD and differentiate. Deletion of Isl1 leads to delayed chorion-allantoic fusion, and defects in vasculogensis of umbilical cord and labyrinth. In this proposal, by using the Isl1 mouse models and human aborted allantois and placenta tissues, we will 1) examine at various developmental stages the number and distribution of Isl1+ progenitors in allantois, placenta and umbilical cord, and characterize the identity and clusters, temporal differentiation pathways, gene and epigenetic profiles and regulatory network of the Isl1+ progenitors; 2) investigate the requirement for Isl1 in allantoic progenitors to contribute to umbilical and placental vasculogenesis and mesenchyme formation, and elucidate underlying mechanisms; 3) investigate the cellular and signaling interactions between chorion plate and allantois and its derivative cells in chorion trophoblast differentiation, villus induction and labyrinth formation. Results of proposed studies will provide novel insight into placenta pathogenesis and associated diseases.